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Am J Physiol Endocrinol Metab 306: E707E722, 2014.
First published December 24, 2013; doi:10.1152/ajpendo.00506.2013.
Review
p21-Activated protein kinases and their emerging roles in glucose homeostasis

Yu-ting Alex Chiang1 and Tianru Jin1,2
1
Department of Physiology, University of Toronto, Toronto, Canada; 2Division of Advanced Therapeutics, University Health
Network, Toronto, Ontario, Canada
Submitted 10 September 2013; accepted in final form 20 December 2013
Chiang YA, Jin T. p21-Activated protein kinases and their emerging roles in
glucose homeostasis. Am J Physiol Endocrinol Metab 306: E707E722, 2014. First
published December 24, 2013; doi:10.1152/ajpendo.00506.2013.p21-Activated
protein kinases (PAKs) are centrally involved in a plethora of cellular processes and
functions. Their function as effectors of small GTPases Rac1 and Cdc42 has been
extensively studied during the past two decades, particularly in the realms of cell
proliferation, apoptosis, and hence tumorigenesis, as well as cytoskeletal remodeling and related cellular events in health and disease. In recent years, a large number
of studies have shed light onto the fundamental role of group I PAKs, most notably
PAK1, in metabolic homeostasis. In skeletal muscle, PAK1 was shown to mediate
the function of insulin on stimulating GLUT4 translocation and glucose uptake,
while in pancreatic -cells, PAK1 participates in insulin granule localization and
vesicle release. Furthermore, we demonstrated that PAK1 mediates the cross talk
between insulin and Wnt/-catenin signaling pathways and hence regulates gut
proglucagon gene expression and the production of the incretin hormone glucagonlike peptide-1 (GLP-1). The utilization of chemical inhibitors of PAK and the
characterization of Pak1/ mice enabled us to gain mechanistic insights as well as
to assess the overall contribution of PAKs in metabolic homeostasis. This review
summarizes our current understanding of PAKs, with an emphasis on the emerging
roles of PAK1 in glucose homeostasis.
GLP-1; insulin; PAK1; Wnt
Overview of the p21-Activated Protein Kinases

P21-ACTIVATED PROTEIN KINASES (PAKs) are serine/threonine
kinases that execute a multitude of cellular and physiological
functions. PAK1, the prototype of the family, was initially
discovered in 1994 as a novel effector of small GTPases (114).
PAKs have been extensively studied as part of numerous
intricate and interconnecting signaling networks that regulate
important cellular activities, including cell proliferation, apoptosis, and cytoskeleton dynamics (15, 20, 59, 122). Both the
disarrangement of the Pak1 gene and the dysfunctions of PAK
signaling under pathophysiological conditions have been identified, particularly for their involvement in tumorigenesis and
cancer metastasis (44, 97). The potential role of PAK signaling
in the development and progression of neuronal diseases, viral
pathogenesis, and immunity, as well as vascular disorders,
have been suggested as well (54, 75, 86, 87, 96, 127, 133, 189).
In addition to the aforementioned functions of PAKs, there is
emerging evidence implicating the importance of PAKs in metabolic processes, specifically in glucose homeostasis. PAK1 was
found to mediate the effect of insulin on stimulating glucose
uptake in skeletal muscle cells, in facilitating insulin secretion in
pancreatic -cells, and in controlling the production of the
incretin hormone glucagon-like peptide-1 (GLP-1) in the gut
endocrine L cells (29, 74, 84, 181, 195, 196).
Address for reprint requests and other correspondence: T. Jin, Rm. 10-354
Toronto Medical Discovery Tower, 101 College St., Toronto, Ontario, Canada
M5G 1L7 (e-mail: tianru.jin@utoronto.ca).
http://www.ajpendo.org
Here we summarize the functions of PAKs, mainly focusing

on the emerging roles of PAK1 in glucose homeostasis. We
have reviewed the studies to date in the exploration of the
molecular and cellular functions of PAK1 in the muscle,
pancreatic -cells, and intestine endocrine L cells, which
collectively point to an essential metabolic role of PAK1.
These studies have also deepened our functional understanding
of the PAK family, and continued efforts in this field may lead
to the discovery of novel drug targets for type 2 diabetes (T2D)
and other metabolic disorders.
The discovery of PAKs, their structural features, and the
activation mechanism. Guanine nucleotide binding proteins (G
proteins) act as molecular switches that transmit a wide variety
of extracellular stimuli to intracellular signaling cascades. The
majority of the G proteins fall into two categories, namely the
monomeric forms (small GTPases) and the heterotrimeric
membrane-bound complexes (Fig. 1A). Small GTPases are
able to bind to and hydrolyze guanosine triphosphate (GTP).
The Ras superfamily of small GTPases comprises over 150
members. It is further classified into eight families (Fig. 1A).
One of them is the Ras homologous (Rho) family, whose
members are also referred to as p21 GTPases since their
molecular sizes are 21 kDa. Within the Rho family, PAKs
have been identified as downstream effectors of the members
of Rac and Cdc42 subfamilies but not for members of the
RhoA subfamily (Fig. 1A).
PAK1 was discovered as a binding partner and target of Rac
and Cdc42 GTPases in the rat brain in 1994 and was originally
named p65PAK (114). The autophosphorylation and kinase
0193-1849/14 Copyright 2014 the American Physiological Society
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PAK AND GLUCOSE HOMEOSTASIS
Superfamily
Family
Subfamily
Ras
Rho
RhoA
Monomeric
G proteins
GTPase
Ras
Heterotrimeric
G proteins
Rac
Rac1
Cdc42
Rac2
Rab
Arf
Rac3
Ran
RhoG
Rap
Rheb
Rit
PAKs
B
Kinase Domain
Auto-Inhibitory Domain
N
PBD
AID
KD
P21-Binding Domain
Pak1
Pak2
Pak3
PXXP SH3-binding motifs

Group I
PBD
AID
ED-rich regions
Group II
Pak4
PXP SH3-binding motifs
Pak5
KD
Pak6
Rac
Cdc42
CHP
TC10
Wrch-1
hPIP1
LKB1
Merlin
Nck Grb2
PAK1
SKIP
Nischarin
Pix/Cool
Thr109
P
CRIPAK
C
P
P
Ser21 Ser57
P
Tyr131
P
Ser144
P P
P
Thr212
Ser199
Ser204
Akt
Src
P
Thr423
Ser223
Pdk-1
p35/Cdk5 CK2
Cdc2
Erk1/2
SAD-A
Fig. 1. p21-Activated protein kinases (PAKs) are effectors of selected small GTPases. A: majority of GTPases are categorized in monomeric and heterotrimeric forms.
The Ras superfamily contains 8 families, including the Rho family. Within this family, members of the Rac and Cdc42 subfamilies act as upstream activators of PAKs.
B: common features of PAKs include the p21-binding domain (PBD, orange), the catalytic kinase domain (KD, green), and multiple PXXP SH3-binding motifs (brown).
The group I PAK proteins share a common autoinhibitory domain (AID, black). Members of group I PAKs also contain acid-rich domains known as ED-rich regions
(light blue) as well as a noncanonical PXP Pix/Cool SH3-binding motif (dark blue) in the central region. C: illustration of the PAK1 molecule. The small p21 GTPases,
including Rac, Cdc42, CHP, TC10, and Wrch-1, bind to the PBD (orange) and stimulates its activation. Ser21, Ser57, Ser144, Ser149, Ser199, Ser204, and Thr423 are
7 autophosphorylation sites. The adapter proteins Nck and Grb2 bind to 2 PXXP motifs (brown) near the NH2 terminus. The noncanonical PXP motif (light blue) interacts with
the adapter protein Pix/Cool. The endogenous inhibitors of PAK1 include hPIP1, Merlin, LKB1, CRIPAK, and Nischarin, with their sites of interaction as indicated (red line).
AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org
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activity of p65PAK were shown to be stimulated in the presence of activated Cdc42 and Rac, and sequence analysis of
p65PAK revealed its homology with the yeast protein Ste20
(114). p65PAK was later renamed as PAK1, while the other
two members of the family were designated as PAK2 and
PAK3 (15, 16, 118, 175). Together, these three kinases comprise the group I PAKs (Fig. 1B). After the initial discovery of
PAK13, three additional PAKs, namely PAK4 6, were identified in mammals (73). They differ significantly from group I
PAKs in their structural organization and regulation and are
referred to as group II PAKs (Fig. 1B) (47, 73). PAK4 was
identified as a novel link between Cdc42 and actin cytoskeleton, where activated PAK4 can be translocated into the
Golgi and induced fibroblast filopodia formation and actin
polymerization (1). PAK6 was identified as an androgen
receptor (AR) interacting protein, and was suggested to
serve as a negative regulator of the androgen/AR signaling
(204). PAK5 is a brain kinase that promotes neurite growth
and filopodia formation (37).
All PAK members share the NH2-terminal p21 binding
domain (PBD) and the highly conserved COOH-terminal catalytic kinase domain (KD) (Fig. 1B). A unique feature of the
group I PAKs is the autoinhibitory domain (AID), which
overlaps but is not coincident with the PBD. The AID acts as
an inhibitory switch and is critical for the autoinhibition of
group I PAKs. Group I PAKs also possess proline-rich PXXP
and PXP SH3-binding motifs interspersed at the NH2 terminus
and central regions. On the other hand, in the group II PAKs,
these SH3-binding motifs are only found in the central region
(Fig. 1B). In the PAK1 molecule, these proline-rich motifs
interact with the Rac1/Cdc42 activator Pix/Cool (PAK interactive exchange partner/Cloned out of library), as well as
certain adapter proteins, such as Nck and Grb2 (21, 115, 141).
As the most extensively studied member of the PAK family,
the crystal structure of PAK1 in an autoinhibited conformation
was determined in 2000 (100). The currently accepted mechanism of group I PAK activation is a multistage model, where
binding of Cdc42 or Rac to the PBD domain disrupts PAKPAK dimerization, leading to a series of conformational
changes that destabilize the folded structure of the inhibitory
switch and thereby inducing the dissociation of the two PAK
molecules (100). Once freed from each other, the individual
PAK molecule may undergo sequential autophosphorylation
steps leading to its full activation.
PAK1 contains seven autophosphorylation sites (Fig. 1C)
(113). Shortly after the discovery of PAK1, the Thr423 residue
located within the activation loop was identified to act as a
critical determinant of PAK1 activation by p21 GTPases and
the lipid sphingosine (209). The T423A PAK1 mutant, which
is unable to be autophosphorylated at this residue, showed
substantially reduced kinase activity following Cdc42 activation (209). With the use of biochemical methods, PAK1 autophosphorylation at Thr423 was demonstrated to occur as an
intermolecular event, where an active PAK1 can trans-autophosphorylate another PAK1 molecule (92). Since then, PAK1
Thr423 phosphorylation, assessed by Western blotting using
commercially available antibodies, has served as an indicator
of its activation in numerous studies (29, 45, 52, 111, 126, 135,
164, 197, 199, 212).
Positive and negative regulators of PAK1. Multiple positive
and negative regulators of PAK1 have been identified (Fig. 2).
Other than Rac1 and Cdc42, PAK1 can also be activated by
certain atypical Rho members, including CHP, TC10, and
Wrch-1 (3, 156, 162, 172) (Fig. 2). The CHP/PAK1/PIX
signaling has been shown to regulate cell adhesion during
zebrafish embryonic development (174). TC10 was found to
activate PAK1 in assessing insulin-stimulated prolactin gene
expression in the rat pituitary GH4 cells (162). Wrch-1 is a
Wnt-1-stimulated small GTPase, which stimulates PAK1
Thr423 phosphorylation in the COS-7 cell line (172).
Positive regulators
p21
GTPases
Rac1
Cdc42
CHP
TC10
Wrch-1
Tumorigenic
factors
Growth
factors
Thrombin
EGF
PDGF
IGF-1
Negative regulators
Hormones
Estrogen
Insulin
Endogenous
inhibitors
SKIP
Merlin
LKB1
CRIPAK
Nisharin
hPIP1
PAK1
Fig. 2. Positive and negative regulators of PAK1. Small p21 GTPases, including Cdc42 and Rac1, as well as atypical ones CHP, TC10, and Wrch-1, can stimulate
PAK1. PAK1 can also be activated by other upstream factors, including tumorigenic factors, growth factors, and hormones such as insulin. Several endogenous
inhibitors of PAK1 have been identified, including the kinase LKB1, the phosphatase SKIP, and other factors such as Merlin, CRIPAK, Nischarin, and hPIP1.
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In addition to these small GTPases, other proteins including

tumorigenic factors, growth factors, and hormones, have been
demonstrated to activate PAK1 (Fig. 2). Thrombin-stimulated
PAK1 activation was observed in vascular smooth muscle
cells, and expression of the kinase-dead PAK1 mutant was
shown to attenuate stress fiber formation and cell migration
(193). The epidermal growth factor (EGF) stimulates PAK1
activation in breast cancer cells, and expression of a dominantnegative PAK1 was shown to attenuate EGF-induced cell
migration (205). PAK1 serves as a convergence point for
platelet-derived growth factor (PDGF) and lysophosphatidic
acid in regulating collagen matrix contraction in human fibroblasts (146). Overexpression of PDGF is known to stimulate
Erk activity in medulloblastoma cells, and this was found to be
mediated through the PAK1-MEK-Erk signaling cascade
(208). PAK1 was also shown to mediate the function of
estrogen in stimulating FKHR phosphorylation, leading to
FKHR nuclear exclusion and the inhibition of cell apoptosis
(119). Notably, the growth factor insulin-like growth factor-1
(IGF-1), as well as the metabolic hormone insulin, were found to
activate PAK1 as well (Fig. 2). IGF-1 activates RUNX2, a
transcription factor that promotes endothelial cell migration, invasion, and proliferation. PAK1 inhibition attenuates RUNX2
DNA-binding (142). Furthermore, insulin has been demonstrated to stimulate PAK1 activity in the skeletal muscle and in
intestinal cells, which are detailed below in Role of PAK1 in
Glucose Transport in the Skeletal Muscle and PAK1 as a
Linker for the Cross Talk Between Insulin and Wnt Signaling
Pathways.
Several endogenous negative regulators of PAK1 have also
been recognized (Fig. 1C and Fig. 2). The skeletal muscle and
kidney enriched inositol phosphatase (SKIP) binds to the KD
of PAK1 and inhibits its scaffolding activity (66). Merlin, encoded by the Nf2 tumor-suppressor gene, inhibits PAK1 activation by targeting its PBD (93). The serine threonine kinase LKB1
phosphorylates PAK1 at Thr109, leading to its inactivation (39).
The cysteine-rich inhibitor of PAK (CRIPAK), identified in a
yeast two-hybrid screen, was shown to suppress PAK1-mediated estrogen receptor transactivation in breast cancer cells
(170). The integrin binding partner Nischarin inhibits PAK1
activity and PAK1-mediated cell migration through its direct
interaction with the PAK1 COOH-terminal domain (2). The
human G-like WD-repeat protein (hPIP1) binds to the PAK1
NH2-terminal regulatory domain, which abolishes Cdc42/Racstimulated PAK1 activity (202).
The mechanisms underlying Pak1 transcriptional regulation
remain largely unknown, although the increase in Pak1 gene
copy number has been reported in certain tumor cells (22, 129).
One study has demonstrated that the microRNA miR-7 binds to
the 3=-untranslated region of Pak1 mRNA and may repress
Pak1 expression in human carcinoma cells (145).
An overview of cellular functions of PAK1. Here, we present
a brief overview of the cellular functions of PAK1 (Fig. 3). An
extensive body of knowledge exists for the downstream effects
of PAK signaling, which have been described in detail elsewhere (9, 20, 26, 44, 59, 122). PAK1 exerts its prosurvival and
antiapoptotic functions via a battery of downstream targets,
including Raf1, NFB, FKHR, BimL, and DLC1 (17, 35, 48,
51, 119, 188) (Fig. 3, column 1). PAK1 is centrally involved in
cytoskeleton remodeling, either by phosphorylating kinases
that regulate actin dynamics, such as LIMK, or by phosphorylating factors and kinases that are involved in actin-based cell
motility, such as myosin light chain (MLC), myosin heavy
chain (MHC), and MLC kinase (MLCK) (24, 28, 33, 36, 144,
PAK1
(1)
(2)
(3)
(4)
(5)
Cell survival
and apoptosis
Cytoskeleton
remodeling
Cell cycle
progression
Immunity
and infection
Transcription and
mRNA splicing
Raf1
LIMK
Aurora
Nck
FKHR
NFB
Myo3p
PIK1
Erk
CtBP1
FKHR
RLC
histone H3
CtBP1
SHARP
BimL
MLC
cyclinD1
Snail
DLC1
MHC
NFB
histone H3
MLCK
MEK1
-cat
PP2A
Raf1
Fig. 3. A general overview of cellular functions of PAK1. PAK1 regulates the following: column 1: cell survival and apoptosis; column 2: cytoskeleton
remodeling; column 3: cell cycle progression; column 4: immunity and infection; as well as column 5: gene transcription and mRNA splicing.
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152, 190, 199, 201, 210) (Fig. 3, column 2). In mast cells,
PAK1 was shown to directly interact with and activate the
phosphatase PP2A in regulating F-actin rearrangement and
mast cell granulation (163) (Fig. 3, column 2). Mast cells from
PAK1/ mice showed abnormal cortical F-actin structures
and granules and impaired allergic responses (163). The effectors of PAK1 in regulating cell cycle progression are listed in
Fig. 3, column 3, including the mitotic regulators cyclin D1,
NF-B, Aurora, and Polo-like 1 (PlK1) (17, 35, 117, 211), the
chromatin protein component histone H3 (99), and the components of the mitogen-activated protein kinase cascade MEK1
and Raf1 (18, 50, 91, 171, 180). The targets that mediate the
function of PAK1 in regulating immune functions and hostpathogen responses are listed in Fig. 3, column 4. PAK1
activates Nck and Erk during T-cell activation, and PAK1
phosphorylates CtBP1 during adenovirus entry (6, 105, 149,
203) (Fig. 3, column 4). Finally, PAK1 is increasingly recognized to participate in nuclear events in regulating gene transcription and mRNA splicing (Fig. 3, column 5). Three nuclear
localization signals have been identified in the PAK1 NH2
terminus, which are required for its nuclear translocation (158).
In the nucleus, PAK1 modulates transcriptional regulators,
such as FKHR, CtBP, SHARP, and Snail, and directly regulates chromatin rearrangement through its interaction with
histone H3 (101). Notably, PAK1 has been shown to enhance
the transcriptional activity of the nuclear Wnt effector -cat in
carcinoma and noncarcinoma cells (112, 134).
Loss-of-function and gain-of-function studies of PAK1 and
other PAKs. The association between PAK activity and tumorigenesis or metastasis has been intensively investigated (26, 90,
97, 130). The underlying mechanisms include increased Pak
gene copy numbers, hyperactivation of the kinase activity,
dysregulation of upstream regulators, or enhanced nuclear
localization of PAKs (8, 22, 60, 90, 116, 151, 187). Many
studies have been conducted using loss-of-function approaches, such as dominant-negative forms of PAK1, RNA
interference, or chemical inhibitors (27, 49, 108, 134, 164).
During the recent years, several small molecule inhibitors of
PAKs have been identified with varying degrees of specificity
(38, 90, 103, 106). Among these, the chemical inhibitor 2,2=dihydroxy-1,1=-dinaphthyldisulfide (IPA3) has demonstrated
high specificity towards the inhibition of group I PAKs (38).
Gain-of-function approaches have also been utilized in a
number of studies. The expression of various forms of constitutively active PAK1 resulted in the formation of larger lamellipodia and increased mobility of fibroblasts (154). The T423E
constitutively active PAK1 mutant has been used in studying
cell proliferation (134, 153, 177), tumorigenesis (27, 72, 108),
and viral pathogenesis (82, 136).
Pak1/ mice are viable, with various degrees of defects in
their immune, neuronal, pulmonary, and cardiac systems (5,
13, 61, 88, 110, 120, 159, 169). In the absence of a challenge,
fasting plasma glucose levels in Pak1/ mice are comparable
with those of the control littermates. However, in the presence
of a glucose or pyruvate challenge, impaired glucose disposal
was observed in the Pak1/ mice (29, 195). Pak2/ mice are
embryonic lethal at embryonic day 8.5 (9, 59). The PAK3 gene
in humans is associated with X-linked nonsyndromic mental
retardation (9, 59), and the Pak3/ mice show deficits in
memory retention (121). Pak1 and Pak3 double knockout mice
show severely reduced postnatal brain growth, associated with
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other neuronal deficits (63). Pak4/ mice are embryonic

lethal at embryonic day 11, while Pak4/ embryos were
found to carry defects in neuronal differentiation and blood
vessel formation (143). Conditional knockout of Pak4 specifically in the nervous system resulted in neuronal defects, along
with striking differences in brain anatomy in neonatal mice
(178). Lastly, both the Pak5/ mice and the Pak6/ mice are
viable, and the gross morphology of various organs appears to
be normal (104, 124). It has been suggested that this may be
due to the potential redundant functions of PAK5 and PAK6
(104). A comprehensive review on Pak knockout mouse models has been presented recently by Kelly and Chernoff (88).
Role of PAK1 in Glucose Transport in the Skeletal Muscle
In 1996, Tsakiridis et al. (181) revealed the presence of
insulin-responsive renaturable kinases in the mouse differentiated L6 muscle cells. Using histone VI-S as the substrate,
Tsakiridis et al. (181) found that insulin is able to stimulate the
activity of PAK1. Utilizing chemical inhibitors for various cell
signaling molecules, Tsakiridis et al. (181) concluded that
insulin-stimulated PAK1 activation is dependent on the tyrosine kinase activity and the activity of phosphoinositide
3-kinase (PI3K).
Insulin-stimulated glucose uptake by skeletal muscle cells is
a key process in maintaining glucose homeostasis, and this is
accomplished by the recruitment of GLUT4 vesicles to the
plasma membrane. Actin cytoskeleton reorganization is involved in insulin-stimulated GLUT4 vesicle translocation, as
pharmacological agents that disrupt actin dynamics, such as
latrunculin B, inhibited GLUT4 translocation to the plasma
membrane and led to reduced glucose uptake in the muscle
cells (23, 31, 166, 183). Insulin is known to regulate actin
dynamics in cultured muscle cells and in the mouse L6 myotubes (179, 182). The binding of insulin to the insulin receptor
results in the phosphorylation of the insulin receptor substrate-1 (IRS-1), which in turn recruits and activates PI3K. The
insulin signaling cascade bifurcates at PI3K into two arms
consisting of Rac1 and Akt (150). Insulin-induced actin cytoskeleton reorganization in muscle cells requires PI3K activity
(94, 183, 184), and insulin-stimulated GLUT4 translocation
and actin remodeling can be blocked either by depleting Rac1
or by inducing conditions that mimic insulin resistance in
cultured muscle cells (74, 185). Expression of a constitutively
active Rac1 elicited GLUT4 vesicle translocation even in the
absence of insulin, suggesting that the presence of active Rac1
suffices in stimulating GLUT4 translocation, at least in the in
vitro setting (185). Treating cultured muscle cells with glucose
oxidase mimics insulin resistance in vitro, and this leads to the
inhibition of Rac1 activation, accompanied by the loss of
Rac1-mediated PAK1 Thr423 phosphorylation (74). These
observations highlighted the requirement of Rac1 signaling in
insulin-stimulated muscle glucose uptake, involving the process of cytoskeleton remodeling. Consistent with the observations made in the above in vitro investigations, insulin was
demonstrated to stimulate Rac1 activation in mouse skeletal
muscle, and mice with muscle-specific deletion of Rac1 show
reduced insulin-induced GLUT4 vesicle translocation in the
muscle tissue (186).
Another small GTPase, namely RalA, has been reported to
function as the effector of Rac1 in mediating its stimulatory
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effect on muscle glucose uptake. Depletion of RalA using the

small interfering RNA-mediated knockdown approach was
shown to reduce Rac1-stimulated GLUT4 vesicle plasma
membrane translocation in the mouse L6 myotubes (128).
Observations described above indicated the essential role of
Rac1 in mediating the stimulatory effect of insulin on GLUT4
membrane translocation and that PAK1 is among the downstream targets of insulin and Rac1 in the muscle. The generation of Pak1/ mice made the direct assessment of the
contribution of PAK1 in muscle glucose uptake available.
Following insulin injection, muscle samples collected from
Pak1/ mice showed significantly reduced GLUT4 vesicle
translocation to the plasma membrane, when compared with
the muscle samples from age-matched wild-type littermates
(195). Cofilin has been reported to act downstream of the
PAK1 effector LIMK and is critically involved in the regulation of actin filamentsin a marsupial kidney epithelial cell line
(40). In line with the role of PAK1/LIMK/cofilin signaling in
cytoskeletal reorganization in epithelial cells, the skeletal muscle from Pak1/ mice was shown to lack the response to
insulin treatment in stimulating cofilin phosphorylation (195).
A very recent study by Sylow et al. (166) provided extended
evidence that Rac1-PAK1 signaling centrally regulates muscle
glucose uptake in intact muscle tissue. More importantly, this
signaling axis was rendered defective under the insulin-resistant state (166). First, they demonstrated that insulin indeed
stimulates Rac1 and PAK1 activation in both mouse and
human skeletal muscle (166). Pharmacological inhibition of
Rac1 resulted in the loss of insulin-stimulated glucose uptake,
independent of Akt status, in isolated mouse skeletal muscle
(166). Muscle-specific deletion of Rac1 in mice resulted in
reduced insulin-stimulated muscle glucose uptake, associated
with attenuated insulin-stimulated PAK1 Thr423 phosphorylation in the muscle (166). Importantly, skeletal muscle isolated
from high-fat diet-fed mice showed reduced Rac1 expression,
associated with blunted PAK1 Thr423 phosphorylation in
response to insulin treatment (166). These observations in the
experimental animals were at least partially recapitulated in
humans, where skeletal muscle insulin resistance induced via
intralipid infusion resulted in a loss of insulin-stimulated PAK1
Thr423 phosphorylation during a hyperinsulinemic-euglycemic clamp study (166).
Similar to PAKs, the Rho-associated coiled-coil-containing
protein kinases (ROCKs) are serine/threonine kinases that also
act as downstream effectors of certain small GTPases, and
ROCKs have been shown to participate in insulin signaling and
energy homeostasis (62). Inhibition of ROCK1 impaired
GLUT4 translocation, while ROCK1 overexpression lead to an
enhanced insulin-sensitizing effect on glucose transport in
adipocytes (34). In the myoblasts, ROCK1 depletion lead to
attenuated insulin-stimulated glucose transport, associated with
defects in actin cytoskeleton remodeling (34). Taken together,
these observations indicate the involvement of additional small
GTPase effectors, such as ROCKs, in GLUT4 translocation
and glucose transport in the muscle (34, 62, 74).
In addition to insulin activation, muscle contraction represents another mechanism by which muscle glucose uptake can
be stimulated (55). The activity of Rac1 was observed to be
elevated during contraction-stimulated glucose uptake in skeletal muscle, and this was concomitant with enhanced PAK1
Thr423 phosphorylation (167). PAK activation and muscle
glucose uptake following contraction were attenuated by either

Rac1 inhibition or the use of F-actin depolymerizing agents in
vitro, as well as in muscle-specific Rac1/ mice (166, 167).
Furthermore, PAK1 Thr423 phosphorylation was enhanced in
mouse and human skeletal muscle following exercise, whereas
lipid infusion in healthy volunteers impaired PAK1 Thr423
phosphorylation. These observations collectively suggest that
Rac/PAK1 signaling plays a role in muscle glucose disposal
during exercise (166, 167).
As aforementioned, Akt2 is another arm of insulin signaling
after its bifurcation at PI3K (150). In 2002, a 160-kDa substrate
of Akt was identified in 3T3L1 adipocytes, known as AS160
(85). It is a protein that contains a Rab GTPase-activating
protein (GAP) domain. Upon insulin stimulation, Akt2 transmits the signal to AS160, which in turn activates the small
GTPases Rab8A and Rab13, and ultimately induce GLUT4
vesicle release (71, 165). Both the Rac1 arm and the Akt2 arm
upregulate glucose uptake in the skeletal muscle, and it has
been proposed that each arm act independently of each other in
promoting GLUT4 vesicle translocation (150, 168). Furthermore, the joint requirement of both arms in insulin-stimulated
GLUT4 translocation has been suggested, where pharmacological inhibition of both Akt2 and Rac1 signaling cascades was
shown to be required to completely block insulin-stimulated
glucose uptake in mouse muscle cells (168). In addition, both
Akt2 and Rac1 signaling pathways were found to be dysfunctional in the muscle tissue of the insulin-resistant ob/ob mouse
model (168). Interestingly, in examining the involvement of
PAK1 as the effector of Rac1 signaling, muscle tissue isolated
from Akt2/ mice appear to have blunted insulin-stimulated
PAK1 Thr423 phosphorylation, while pharmacological inhibition of Akt2 does not alter PAK1 activation (168). To explain
this obvious discrepancy, it has been proposed that although
the Rac1 and Akt2 arms do not cross talk with each other in
regulating glucose uptake, the presence of Akt2 is still required
for the activation of the Rac1 cascade (168).
The essential role of Rac1 in regulating actin dynamics
underlying muscle glucose uptake has been demonstrated in
numerous investigations (31, 74, 150, 185). Although PAK1
has been shown to regulate actin filament dynamics in a
number of other cell types, including neuronal cells and pancreatic -cells (detailed in the sections below) (57, 98, 140,
163), the direct effect of PAK1 on actin remodeling in muscle
cells remains to be examined.
Role of PAK1 in Insulin Secretion
Following food consumption or glucose stimulation, insulin
is released from pancreatic -cells in two distinct phases,
known as biphasic insulin secretion. The first phase is triggered
by the elevation of intracellular calcium levels, leading to the
fusion of predocked insulin-containing granules to the plasma
membrane. The second phase involves the mobilization of
stored granule pools to the cell surface, which represents the
sustained insulin release following glucose stimulation.
As demonstrated by Wang et al. (196), Cdc42/Rac1 signaling is evidently involved in the insulin secretion process, as
Cdc42 knockdown selectively attenuated the second phase of
glucose-stimulated insulin secretion (GSIS) in rodent pancreatic -cell lines and in isolated mouse and human pancreatic
islets. In the mouse pancreatic -cell line MIN6, Cdc42 acti-
Review
vation was detected in response to D-glucose treatment but not

to potassium chloride (KCl) or the nonmetabolizable glucose
analogs (196). Furthermore, Cdc42 activation in response to
high glucose treatment preceded Rac1 activation at the plasma
membrane, and PAK1 Thr423 phosphorylation was observed
to be Cdc42-dependent but Rac1 independent (196). Knockdown of PAK1 expression in the mouse -cell line using the
small interference RNA knockdown approach abolished
Cdc42-mediated Rac1 activation (196). These observations
collectively implicate the existence of the Cdc42-PAK1-Rac1
axis during the second phase of GSIS in the pancreas (196),
which differs from the Cdc42-Rac1-PAK1 signaling observed
in the skeletal muscle cells in terms of the sequential order of
activation of the signaling components (74).
To further assess the role of PAK1 in insulin secretion and
to explore its pathophysiological implications, Wang et al.
(195) conducted further investigations. They demonstrated that
PAK1 protein levels are reduced in islets of T2D patients
(195). In human islets and a rodent pancreatic -cell line, IPA3
pretreatment was shown to elicit a defect in the second phase
of GSIS (195). Wang et al. (195) then revealed that Pak1/
islets exhibited attenuated second phase of GSIS, associated
with impaired glucose and insulin tolerance in the Pak1/
mice. To identify downstream effectors of PAK1 during GSIS,
Wang et al. (195) performed PAK1 small interference RNA
knockdown in a pancreatic -cell line and observed an abolished glucose-induced Erk activation. This event was also
partially recapitulated in pancreatic islets isolated from the
Pak1/ mice (195, 196).
Although PAK1 has been widely accepted as a positive
regulator of cell proliferation, the Pak1/ mice lack notable
defects in pancreatic -cell mass and abnormalities in islet
morphology, as observed by both Wang et al. (195) and by our
group (29).
The importance of F-actin remodeling in GSIS has been
recognized for 40 yr, where F-actin filaments were shown to
act as barriers at the plasma membrane to prevent the docking
and fusion of insulin granules under unstimulated conditions
(14, 131, 191). Rac1 and a number of other small GTPases
have been implicated in various functions of pancreatic -cells,
including the secretion of insulin at different steps (95). In a
murine -cell line, Rac1 activation was shown to be stimulated
by high glucose treatment (102). The expression of a dominant-negative Rac1 in -cells abolished its cytosol-to-membrane translocation upon high glucose stimulation, which was
associated with reduced GSIS (102). Very recently, Asahara et
al. (12) demonstrated the role of Rac1 in regulating GSIS via
modulating F-actin using both in vitro and in vivo approaches.
In the pancreatic -cell line MIN-6, Rac1 activation was
observed following high glucose treatment (12). Rac1 knockdown leads to the persistence of intact F-actin in the presence
of high glucose, associated with reduced insulin secretion
following glucose stimulation (12). The study utilizing islets
isolated from -cell-specific Rac1/ mice also recapitulated
the observations of defective insulin secretion following high
glucose treatment, without significant alterations in islet morphology (12).
Although PAK1 is evidently involved in the second phase of
GSIS, the exact mechanism by which PAK1 evokes F-actin
remodeling in response to glucose is still not completely
understood. An early study identified the role of the Cdc42-
E713
PAK1-Rac1 axis in regulating F-actin rearrangement and insulin secretion in -cells (196). It was further demonstrated
that glucose-induced cortical F-actin remodeling also involves the Cdc42-PAK1-MEK-Erk pathway and that glucose-induced insulin granule exocytosis can be blocked by
the PAK inhibitor IPA3 (83, 84). The downstream effects of
the PAK1-MEK-Erk signaling cascade may include MLCK,
an actin-associated kinase that has been implicated in -cell
insulin secretion (11, 83).
In a recent live cell imaging study, Kalwat et al. (84) have
further elucidated the mechanistic requirement of PAK1 in
glucose-stimulated insulin granule exocytosis. Pretreatment of
mouse pancreatic -cells with IPA3 inhibited glucose-induced
F-actin remodeling and ablated glucose-stimulated insulin
granule localization to the plasma membrane (84). In mouse
-cells, glucose treatment stimulated Raf1 phosphorylation
and activation, while IPA3 treatment or Cdc42 inhibition
abolished this activation (84). Similarly, IPA3 treatment
blunted MEK to Erk signaling, while the presence of a MEKErk inhibitor disrupted F-actin remodeling and resulted in
defective insulin granule release (84). Altogether, these in vitro
findings implicate the functional requirement of PAK1 in
relaying the signal of Cdc42 to the downstream Raf1-MEKErk cascade, which potentiates insulin granule mobilization
through F-actin remodeling (84).
Despite the substantial evidence supporting the notion that
Cdc42-PAK1 signaling participates in insulin granule mobilization, the effect is still needed to further clarify how Cdc42
activation, in response to high glucose treatment, leads to
PAK1 activation in pancreatic -cells The synapses of amphids
defective (SAD-A) kinase is a serine/threonine kinase closely
related to the AMP-activated kinases (4). SAD-A is exclusively expressed in the brain and pancreas and has been
implicated in synaptic function and neuronal development
(68). In examining the role of SAD-A in insulin secretion, Nie
et al. (126) first showed that treatment with high glucose
induces SAD-A activation and SAD-A can stimulate PAK1
Thr423 phosphorylation and PAK1 kinase activity in a murine
pancreatic -cell line. SAD-A was also shown to interact with
recombinant GST-PBD of PAK, which can be completely
abolished by a point mutation that inactivates the SAD-A
kinase activity (126). Overexpression of SAD-A led to enhanced cortical F-actin formation, while expression of a kinase-dead SAD-A K48M mutant induced cortical actin filament disintegration (126). Importantly, short hairpin RNAmediated SAD-A knockdown attenuated GSIS in the mouse
-cell line MIN-6, and adenoviral expression of either K48M
SAD-A or the dominant-negative PAK1 mutant K299R was
able to significantly reduce GSIS in mouse islets (126). Taken
together, SAD-A is at least among the direct upstream activators of PAK1 in regulating insulin granule exocytosis in
-cells. SAD-A has been postulated as the downstream effect
of PKA and calmodulin-dependent protein kinase kinase
(CaMMK) (126), while the relationship between SAD-A and
Rac1 remains to be investigated.
PAK1 as a Linker for the Cross Talk Between Insulin and
Wnt Signaling Pathways
Although it is still under debate after intensive investigations
for a number of years, certain epidemiological studies have
Review
E714
implicated an association among obesity, metabolic syndrome,

and the development of various types of tumors, including
those in the mammary gland and the large intestine (7, 19, 157,
192, 200). It has been postulated that the molecular basis for
this association is the aberrant insulin signaling, resulting in the
stimulation of cell proliferation and tumorigenesis in the context of T2D (43, 109, 164, 198). The canonical Wnt signaling
pathway positively regulates cell proliferation, and its dysregulated activation is strongly associated with tumors of various
origins. The clinical and epidemiological correlations between
T2D and the cancer risk have been summarized in numerous
excellent review articles (42, 46, 69, 70, 77, 79, 81, 132, 160).
Activation of the canonical Wnt signaling pathway occurs
upon the binding of a Wnt ligand to the Frizzled receptor and
low-density lipoprotein receptor-related protein 5 and 6 (LRP5/
6), the coreceptor of the Wnt ligands. This triggers a series of
signaling events, ultimately leading to the nuclear translocation
of free -catenin (-cat) (78). Nuclear -cat will subsequently
interact with a member of the TCF transcription factor family,
forming the bipartite transcription factor -cat/TCF. Among
the four known TCF members, TCF7L2 has been recognized
as an important diabetes risk gene(56). A number of proproliferative genes, such as c-Myc and cyclin D1, are known
downstream targets of -cat/TCF. In addition, our group has
demonstrated that -cat/TCF positively regulates the expression of the proglucagon gene (gcg) in the gut endocrine L cells.
PAK1 has been shown to serve as a downstream effector of
insulin and IGF-1 (89, 142, 147, 181). In both breast cancer
and colon cancer patients, increased PAK1 copy number has
been reported (22, 129). In addition, the upregulation of PAK
activity has been associated with the progression and metastasis of various types of tumors (26, 90, 97, 130). It is therefore
plausible to propose that PAKs may act as the linker between
insulin/IGF-1 and Wnt signaling pathways. In supporting this
hypothesis, a battery of in vitro investigations conducted by
our group and others have shown that PAK1 mediates the
stimulatory effect of insulin on the proliferation of intestinal
tumorous and nontumorous cells, involving the -cat/TCF
transcriptional activity (29, 89, 147, 164).
Both insulin and IGF-1 were shown to stimulate PAK1
Thr423 phosphorylation in different cell lineages (29, 147,
164, 181), and we have demonstrated that intraperitoneal
injection of insulin in the FVB mice resulted in insulinstimulated PAK1 Thr423 phosphorylation in the liver, fat,
heart, as well as small and large intestines (164). In the
intestinal carcinoma cell lines, expression of dominant-negative K299R PAK1 attenuated insulin-stimulated c-Myc and
cyclin D1 protein expression, while expression of constitutively active T423E mutant PAK1 increased c-Myc and cyclin
D1 protein levels following insulin stimulation (164). The
expression of K299R dominant-negative PAK1 also led to
reduced insulin-stimulated binding of -cat/TCF to the human
c-Myc gene promoter (164). Furthermore, PAK1 knockdown
resulted in a drastic reduction of c-Myc and cyclin D1 expression, accompanied by attenuated Erk1/2 phosphorylation in the
presence and absence of insulin stimulation (164). Finally,
insulin treatment was shown to increase -cat phosphorylation
at Ser675, an event that is positively correlated with -cat
nuclear translocation and -cat/TCF transcriptional activity
(58, 164, 173). In contrast, PAK1 knockdown attenuated insulin-stimulated -cat Ser675 phosphorylation, associated with
reduced binding of -cat to the c-Myc gene promoter, and

repressed c-Myc gene expression (164). Recently, in vitro
biochemical studies have demonstrated a direct interaction
between PAK1 and -cat, where PAK1 was shown to stimulate
-cat Ser675 phosphorylation in breast cancer and colon cancer cells (10, 213). These findings collectively implicate that
mechanistically PAK1 acts as a linker between insulin and Wnt
signaling pathways.
Role of PAK1 in Proglucagon Gene Expression, GLP-1
Production, and Secretion
The role of Wnt signaling pathway in metabolic homeostasis
has captured our attention during the last decade (30, 79).
Hence, we have been exploring the metabolic effect of the
cross talk between Wnt and insulin signaling pathways (125,
155, 206, 207).
The proglucagon gene (gcg) is expressed in pancreatic
cells, intestinal endocrine L cells, and certain neuronal cells in
the brainstem. The gcg gene encodes several important peptide
hormones, including the incretin hormone GLP-1, which is
mainly produced in the gut and brain but not in the pancreas
(25). Lithium treatment, which mimics Wnt ligand activation
(161), was shown to stimulate gcg transcription and GLP-1
synthesis in the intestinal L cells, while the expression of a
dominant-negative TCF7L2 abolished lithium-induced gcg
transcription and GLP-1 production. More recently, we found
that the Wnt ligand Wnt3a can also stimulate gcg promoter
activity and increase gcg mRNA levels in the mouse intestinal
endocrine L cell line GLUTag (29). Although insulin was
shown to repress gcg expression in pancreatic -cells (137,
138), it activates gcg transcription in the gut GLP-1-producing
cells, and this activation was found to be PI3K dependent but
Akt independent (207). Furthermore, insulin treatment was
shown to stimulate gcg promoter activity, and this stimulation
depends on the TCF binding motif within the G2 enhancer
element. The G2 enhancer element is known to mediate -cat/
TCF- or Wnt ligand-stimulated gcg promoter activity. Indeed,
insulin treatment enhanced binding of -cat/TCF7L2 to the G2
enhancer element (207). Thus the cross talk between insulin
signaling and the Wnt signaling pathway effectors -cat/
TCF7L2 represents a novel mechanism underlying the transcriptional regulation of gut gcg expression and GLP-1 production (76).
Considering that PAK1 functions as a mediator for the cross
talk between insulin and Wnt signaling pathways in the gut
endocrine and nonendocrine cells as well as elsewhere (147,
164), we asked whether PAK1 plays a role in regulating gut
and brain gcg expression and GLP-1 production. We first of all
verified that insulin treatment indeed stimulates PAK1 Thr423
phosphorylation in both the mouse intestinal endocrine L-cell
line GLUTag and a hypothalamic gcg-expressing neuronal cell
line (29). We then found that insulin treatment also stimulated
-cat Ser675 phosphorylation in these two cell lines (29). In
the GLUTag cell line, IPA3 was shown to block the stimulation of insulin on -cat Ser675 phosphorylation, associated
with attenuated gcg promoter activity and gcg mRNA expression following insulin stimulation (29). We then expanded the
investigation to investigate the physiological implications of
PAK1 in GLP-1 production and function utilizing the Pak1/
mice (29). Pak1/ mice exhibited impaired tolerance to
Review
glucose as well as pyruvate challenge (29). Furthermore,

Pak1/ mice show drastically lower levels of intestinal and
brain gcg mRNA, associated with reduced distal ileum GLP-1
content, and decreased circulating insulin and GLP-1 levels
following oral glucose challenge (29). These in vivo observations demonstrated that PAK1 ablation leads to the impairment
of glucose homeostasis, as well as defective insulin and GLP-1
responses following glucose challenge (29). As PAK1 regulates gut gcg expression, the reduction in gut gcg expression in
the Pak1/ mice likely contributes, at least partially, to the
overall glucose intolerance (29).
In the intestinal endocrine L cells, PAK1 was also verified to
be the target of Cdc42, where Cdc42 and PAK are required for
insulin-induced actin remodeling (107). In the mouse gut
GLUTag cell line, chemical reagents that disrupt filamentous
actin potentiated GLP-1 secretion, whereas the knockdown of
either Cdc42 or PAK1 attenuated actin remodeling and GLP-1
secretion (107). Hence, activation of the Cdc42/PAK1 signaling cascade and the consequent actin remodeling events also
positively regulate GLP-1 secretion, at least in the in vitro
setting (107).
Summary, Disputes, and Perspectives
Originally identified as effectors of selected small GTPases
including Cdc42 and Rac1, the PAK family of protein kinases
have been shown to carry out a plethora of functions in various
cell lineages, including cell proliferation and apoptosis, cytoskeleton remodeling, cell cycle progression, and gene transcription. The exploration of these general cellular functions of
PAKs, especially its prototype PAK1, has been further expanded into the field of metabolic research, revealing the
fundamental role of PAK1 in glucose homeostasis during
health and disease. PAK1 is expressed in multiple metabolic
tissues, and it evidently functions as an important metabolic
regulator. A schematic overview of the current knowledge on
the role of PAK1 in glucose homeostasis is presented in Fig. 4,
focusing on its role in glucose uptake in the skeletal muscle, in
insulin secretion in the pancreatic islets, and in the production
and function of the incretin hormone GLP-1 in the intestine.
Upon food intake, the rise in plasma glucose levels leads to
the postprandial release of insulin. The insulin/IRS-1/PI3K
signaling not only activates Akt2, which utilizes AS160 and
Rab proteins to stimulate glucose uptake (176), but also activates the Cdc42-Rac1-PAK1 signaling axis in regulating
GLUT4 vesicle translocation (Fig. 4, left). Actin remodeling is
a key process underlying GLUT4 vesicle translocation, which
provides the mechanistic basis for glucose uptake. The Rac1/
PAK1 signaling plays a fundamental role in insulin-stimulated
GLUT4 vesicle mobilization, and deficiency of either Rac1 or
PAK1 leads to impaired glucose uptake in response to insulin
stimulation. However, it remains unclear as to whether PAK1,
or other downstream effectors of Rac1, or both, mediate the
actin remodeling events in the skeletal muscle cells. In addition, the relationship between the contributions of PI3K-Akt2
signaling vs. PI3K-Rac1-PAK1 signaling in muscle glucose
uptake in response to insulin or exercise needs to be further
explored.
It should be pointed out that, although the majority of studies
to date have focused on assessing PAK1 in the muscle as a
protein kinase, one laboratory has recently suggested a poten-
E715
tial novel mechanism for PAK1 in regulating glucose uptake

(66). The inositiol phosphatase SKIP has been shown to inhibit
insulin/PI3K/Akt signaling and repress insulin-stimulated
GLUT4 translocation as well as glucose uptake in the mouse
L6 myoblasts (64, 65, 67). It has been postulated that the
underlying mechanism involves the binding of SKIP to PAK1,
which blocks PAK1 scaffolding function but not its kinase
activity in mouse myoblasts (66). Hence, the potential dual
function of PAK1 in insulin-stimulated muscle glucose uptake
is worth furtherer exploration.
In pancreatic -cells, the elevation of plasma glucose stimulates postprandial insulin release, and the underlying mechanisms include the activation of the Cdc42-Rac1-PAK1 signaling cascade in the -cells, and the secretion of the gut incretin
hormones, including GLP-1 (Fig. 4, right and middle). Depletion or knockdown of Cdc42 or PAK1 abolished the second
phase of GSIS in the rodent pancreatic -cell line as well as in
mouse and human islets (195, 196). In line with these in vitro
findings, Pak1/ mice were shown to exhibit reduced plasma
insulin levels following glucose challenge (29, 195).
As aforementioned, the role of PAK1 as a scaffold has been
demonstrated in muscle cell glucose uptake (66). A very recent
investigation further showed that overexpression of a kinasedead PAK1 in Hela cells and in the colon cancer cell lines led
to increased MEK and Erk phosphorylation, without affecting
the phosphorylation status of PAK1 downstream targets (194).
In pancreatic -cells, whether the scaffolding function of
PAK1 participates in regulating insulin secretion remains an
open question.
It should be noted that the hierarchical relationship between
PAK1 and the small GTPases could be cell type or tissue
specific. Both the Cdc42-PAK1-Rac1 axis and the Cdc42PAK1-Raf1-MEK-Erk axis have been demonstrated to participate in the regulation of GSIS in pancreatic -cells (196). In
the skeletal muscle cells, as presented in Fig. 4, left, PAK1 was
shown to act downstream of both Cdc42 and Rac1 in regulating
insulin-stimulated glucose uptake (74). In addition to the varying sequence of activation events, the functions of Cdc42 and
Rac1 have been found to vary in other cell lineages. Cdc42 and
Rac1 have been demonstrated to act in antagonistic manners, in
the generation of reactive oxygen species (41), and in the
regulation of cell proliferation (32, 123).
Finally, in the gut endocrine L cells, PAK1 was shown to
regulate both the production and secretion of GLP-1 (29, 107)
(Fig. 4, middle). PAK1-deficient mice express reduced levels
of gcg mRNA in their gut and brain (29). We have revealed
that PAK1 links insulin with the Wnt signaling pathway
effector -cat, leading to the activation of gcg expression and
GLP-1 production in the gut GLP-1-producing cell line
GLUTag (29).
As GLP-1 functions as an incretin, it is difficult to evaluate
the deleterious effect of PAK1 deficiency in the gut endocrine
L cells vs. PAK1 deficiency in the pancreatic -cells on insulin
secretion in the Pak1/ mice. To properly dissect the metabolic function of PAK1 in the gut endocrine L cells vs. the
pancreatic -cells, it will be necessary to generate cell type
specific knockout animal models.
In addition to the skeletal muscle, pancreatic islets, and
intestines, PAK1 is also expressed in tissues including the
brain, liver, heart, and adipocytes, all of which are fundamentally involved in metabolic and glucose homeostasis (29).
Review
E716
FEEDING
Elevated insulin
Elevated glucose
PI3K
Cdc42
Muscle
Pancreas
Cdc42
Akt
PAK1
Rac1
AS160
GLUT4
translocation
Rac1
Insulin
secretion
PAK1
Intestine
Insulin response
Glucose uptake
L cells
PAK1
Cdc42
-cat
PAK1
Gcg
expression
GLP-1
secretion
Bloodstream
GLP-1
Incretin effect
Fig. 4. A summary of current knowledge on the role of PAK1 in glucose homeostasis. Upon feeding, the rise in blood glucose level leads to elevated circulating
insulin levels. In the muscle, insulin stimulates GLUT4 translocation via the phosphoinositide 3-kinase (PI3K)-Cdc42-Rac1-PAK1 signaling axis and the
PI3K-Akt-AS160 axis in promoting muscle glucose uptake (left). In the pancreas, increased blood glucose level elicits the postprandial release of insulin form
the -cells, involving the Cdc42-PAK1-Rac1 signaling cascade (right). The postprandial insulin response is augmented by the incretin hormone glucagon-like
peptide-1 (GLP-1; middle). In the gut L cells, insulin activates the PAK1--cat signaling pathway, leading to the stimulation of gcg transcription and GLP-1
production.
Whether PAK1 in those tissues is also involved in regulating

glucose homeostasis under physiological and pathophysiological conditions is an interesting direction for future research.
The subtle structural differences among the three members
of group I PAKs (Fig. 1B) suggest that they may exert both
unique and overlapping functions. It is notable that the metabolic defects observed in the Pak1/ mice are not drastic. We
have noticed that the impairment in whole body glucose
disposal was absent when the Pak1/ mice are in the C57BL/
6 129 hybrid background (29). Even after the Pak1/ mice
have been backcrossed to the C57BL/6 genetic background, in
the absence of glucose challenge, the basal blood glucose
levels were comparable between the Pak1/ mice and the
control littermates, as demonstrated by our group and by Wang
and colleagues (29, 195). It is reasonable to speculate that

certain metabolic functions of PAK1 in the Pak1/ mice are
compensated by the other two group I PAKs. Indeed, redundant functions of PAK1 and PAK3 have been observed in the
brain neurons (53, 63). Hence, it will be imperative to explore
and define the unique contributions of each of the three group
I PAKs, as well as their redundant functions, with continued in
vitro and in vivo investigations.
Mechanistic exploration of the involvement of PAK1 in
metabolic homeostasis represents an expansion of our fundamental knowledge of the general cellular functions of PAK
proteins. The investigations conducted exploring their role in
cytoskeleton remodeling led us to appreciate the role of PAK1
in muscle cell glucose uptake and in -cell insulin secretion.
Review
The studies deciphering their role in regulating gene expression

prompted us to examine the role of PAK1 in gut gcg expression
and GLP-1 production. In the cancer research field, PAKs have
been shown to function as effectors of growth factors, and they
are evidently involved in stimulating cell proliferation and
inhibiting cell apoptosis. In the Pak1/ mice, we, however,
did not observe noticeable proliferative defects in the pancreatic -cells and elsewhere (29). Again, this suggests that the
other two group I PAKs may compensate the function of PAK1
in the Pak1/ mice. Hence, we will need to employ both
gain-of-function and loss-of-function approaches, under both
in vitro and in vivo settings, to further elucidate whether and
how members of group I PAKs play redundant roles in controlling -cell proliferation. It should be pointed out that PAK3
may coordinate the stress response (148). A very recent study
indicated that PAK3 stimulates cell cycle exit and differentiation of embryonic pancreatic -cells (139). PAK3 is essential
for maintaining glucose homeostasis in response to high-fat
diet challenge (139). Hence, group I PAK members may exert
not only redundant and compensatory function but also opposite functions in pancreatic -cells. This is worthy of further
investigation.
In summary, extensive in vitro and in vivo investigations to
date have uncovered that PAK1 exerts critical functions in the
muscle, pancreas, and gut in regulating glucose disposal. Future exploration, including the expansion of the study into
other PAK members as well as additional metabolic tissues,
will aid in our understanding of the complex regulatory networks underlying glucose homeostasis during health and disease.
ACKNOWLEDGMENTS
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
We regret that we cannot cite other excellent publications related to the

topic in this review article.
18.
GRANTS
The research on PAK1 and Wnt signaling pathway in the laboratory of Dr.
T. Jin has been supported by operating grants from Canadian Institutes of
Health Research (CIHR; MOP-89987 and MOP-97790) and an operating grant
from Canadian Diabetes Association (CDA; OG-3-10-3040).
19.
20.
21.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
22.
AUTHOR CONTRIBUTIONS
Author contributions: Y.-t.A.C. and T.J. conception and design of research;
Y.-t.A.C. prepared figures; Y.-t.A.C. drafted manuscript; Y.-t.A.C. and T.J.
edited and revised manuscript; Y.-t.A.C. and T.J. approved final version of
manuscript.
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Am J Physiol Endocrinol Metab 306: E707E722, 2014.

First published December 24, 2013; doi:10.1152/ajpendo.00506.2013.

p21-Activated protein kinases and their emerging roles in glucose homeostasis

Overview of the p21-Activated Protein Kinases

Here we summarize the functions of PAKs, mainly focusing

0193-1849/14 Copyright 2014 the American Physiological Society

PAK AND GLUCOSE HOMEOSTASIS

PXXP SH3-binding motifs

PXP SH3-binding motifs

PAK AND GLUCOSE HOMEOSTASIS

PAK AND GLUCOSE HOMEOSTASIS

In addition to these small GTPases, other proteins including

other neuronal deficits (63). Pak4/ mice are embryonic

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

PAK AND GLUCOSE HOMEOSTASIS

effect on muscle glucose uptake. Depletion of RalA using the

glucose uptake following contraction were attenuated by either

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

vation was detected in response to D-glucose treatment but not

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

PAK AND GLUCOSE HOMEOSTASIS

implicated an association among obesity, metabolic syndrome,

reduced binding of -cat to the c-Myc gene promoter, and

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

glucose as well as pyruvate challenge (29). Furthermore,

tial novel mechanism for PAK1 in regulating glucose uptake

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

PAK AND GLUCOSE HOMEOSTASIS

Whether PAK1 in those tissues is also involved in regulating

and colleagues (29, 195). It is reasonable to speculate that

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

The studies deciphering their role in regulating gene expression

We regret that we cannot cite other excellent publications related to the

1. Abo A, Qu J, Cammarano MS, Dan C, Fritsch A, Baud V, Belisle B,

Atkinson SJ, Travers JB, Chernoff J, Clapp DW. p21-activated kinase

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

PAK AND GLUCOSE HOMEOSTASIS

47. Eswaran J, Soundararajan M, Kumar R, Knapp S. UnPAKing the

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

PAK AND GLUCOSE HOMEOSTASIS

138. Philippe J. Insulin regulation of the glucagon gene is mediated by an

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

recruitment of glucose transporters to the plasma membrane. J Biol Chem

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

PAK AND GLUCOSE HOMEOSTASIS

202. Xia C, Ma W, Stafford LJ, Marcus S, Xiong WC, Liu M. Regulation

208. Yuan L, Santi M, Rushing EJ, Cornelison R, MacDonald TJ. ERK

AJP-Endocrinol Metab doi:10.1152/ajpendo.00506.2013 www.ajpendo.org

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