Introduction

Signal Transducing Receptor Classes

Receptor Tyrosine Kinases
Non-Receptor Tyrosine Kinases
Receptor Serine/Threonine Kinases
Non-Receptor Serine/Threonine Kinases
Phospholipids and Phospholipases
G-Protein Coupled Receptors
G-Protein Regulators
Intracellular Hormone Receptors
Phosphatases
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Mechanisms of Signal Transduction
Signal transduction at the cellular le!el re"ers to the mo!ement o" signals
"rom outside the cell to inside# The mo!ement o" signals can $e simple%
li&e that associated 'ith receptor molecules o" the acetylcholine class(
receptors that constitute channels 'hich% upon ligand interaction% allo'
signals to $e passed in the "orm o" small ion mo!ement% either into or out
o" the cell# These ion mo!ements result in changes in the electrical
potential o" the cells that% in turn% propagates the signal along the cell#
More comple) signal transduction in!ol!es the coupling o" ligand-receptor
interactions to many intracellular e!ents# These e!ents include
phosphorylations $y tyrosine &inases and/or serine/threonine &inases#
Protein phosphorylations change en*yme acti!ities and protein
con"ormations# The e!entual outcome is an alteration in cellular acti!ity
and changes in the program o" genes e)pressed 'ithin the responding
cells#
Please re"er to the page on Gro'th +actors "or descriptions o" the gro'th
"actors descri$ed in this page and the e)planation o" their a$$re!iations#
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Classifications of Signal Transducing
Receptors
Signal transducing receptors are o" three general classes(
1. Receptors that penetrate the plasma mem$rane and ha!e
intrinsic en*ymatic acti!ity Receptors that ha!e intrinsic en*ymatic
acti!ities include those that are tyrosine kinases ,e#g# P-G+%
insulin% .G+ and +G+ receptors/% tyrosine phosphatases ,e#g#
C-01 2cluster determinant-453 protein o" T cells and macrophages/%
guanylate cyclases ,e#g# natriuretic peptide receptors/ and
serine/threonine kinases ,e#g# acti!in and TG+- receptors/#
Receptors 'ith intrinsic tyrosine &inase acti!ity are capa$le o"
autophosphorylation as 'ell as phosphorylation o" other su$strates#
4dditionally% se!eral "amilies o" receptors lac& intrinsic en*yme acti!ity% yet
are coupled to intracellular tyrosine &inases $y direct protein-protein
interactions ,see $elo'/#
2. Receptors that are coupled% inside the cell% to GTP-$inding and
hydroly*ing proteins ,termed G-proteins/# Receptors o" the class that interact
'ith G-proteins all ha!e a structure that is characteri*ed $y 5 transmem$rane
spanning domains# These receptors are termed serpentine receptors# .)amples
o" this class are the adrenergic receptors% odorant receptors% and certain
hormone receptors ,e#g# glucagon% angiotensin% !asopressin and $rady&inin/#
. Receptors that are "ound intracellularly and upon ligand $inding migrate
to the nucleus 'here the ligand-receptor comple) directly a""ects gene
transcription#
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Receptor Tyrosine !inases "RT!s#
The proteins encoding RTKs contain "our ma6or domains(
4n e)tracellular ligand $inding domain#
4n intracellular tyrosine &inase domain#
4n intracellular regulatory domain#
4 transmem$rane domain#
The amino acid se7uences o" the tyrosine &inase domains o" RTKs are
highly conser!ed 'ith those o" c4MP-dependent protein &inase ,$!%/
'ithin the 4TP $inding and su$strate $inding regions# Some RTKs ha!e an
insertion o" non-&inase domain amino acids into the &inase domain termed
the &inase insert# RTK proteins are classi"ied into "amilies $ased upon
structural "eatures in their e)tracellular portions ,as 'ell as the presence
or a$sence o" a &inase insert/ 'hich include the cysteine rich domains%
immunoglo$ulin-li&e domains% leucine-rich domains% Kringle domains%
cadherin domains% "i$ronectin type III repeats% discoidin I-li&e domains%
acidic domains% and .G+-li&e domains# ased upon the presence o" these
!arious e)tracellular domains the RTKs ha!e $een su$-di!ided into at
least 80 di""erent "amilies#
Characteristics of the Common Classes of
RT!s
Class &'amples Structural (eatures of Class
I
.G+ receptor%
N.9/H.R:% H.R;
cysteine-rich se7uences
II
insulin receptor%
IG+-8 receptor
cysteine-rich se7uences< characteri*ed $y
disul"ide-lin&ed heterotetramers
III
P-G+ receptors% c-
Kit
contain 1 immunoglo$ulin-li&e domains<
contain the &inase insert
I= +G+ receptors
contain ; immunoglo$ulin-li&e domains as
'ell as the &inase insert< acidic domain
=
!ascular endothelial
cell gro'th "actor
,=.G+/ receptor
contain 5 immunoglo$ulin-li&e domains as
'ell as the &inase insert domain
=I
hepatocyte gro'th
"actor ,HG+/ and
scatter "actor ,SC/
receptors
heterodimeric li&e the class II receptors
e)cept that one o" the t'o protein su$units
is completely e)tracellular# The HG+
receptor is a proto-oncogene that 'as
originally identi"ied as the Met oncogene
=II
neurotrophin
receptor "amily ,tr&4%
tr&% tr&C/ and NG+
receptor
contain no or "e' cysteine-rich domains<
NG+R has leucine rich domain
Many receptors that ha!e intrinsic tyrosine &inase acti!ity as 'ell as the
tyrosine &inases that are associated 'ith cell sur"ace receptors contain
tyrosines residues% that upon phosphorylation% interact 'ith other proteins
o" the signaling cascade# These other proteins contain a domain o" amino
acid se7uences that are homologous to a domain "irst identi"ied in the c-
Src proto-oncogene ,c - designates the cellular "orm o" proto-onogenes
that 'ere "irst identi"ied in trans"orming retro!irus/# These domains are
termed S)2 domains ,Src homology domain :/# 4nother conser!ed
protein-protein interaction domain identi"ied in many signal transduction
proteins is related to a third domain in c-Src identi"ied as the S) domain#
The interactions o" SH: domain containing proteins 'ith RTKs or receptor
associated tyrosine &inases leads to tyrosine phosphorylation o" the SH:
containing proteins# The result o" the phosphorylation o" SH: containing
proteins that ha!e en*ymatic acti!ity is an alteration ,either positi!ely or
negati!ely/ in that acti!ity# Se!eral SH: containing proteins that ha!e
intrinsic en*ymatic acti!ity include phospholipase C- "$*C-#% the proto-
oncogene c-Ras associated GTPase acti!ating protein ,rasG%$/%
phosphatidylinositol--kinase "$+-!#% protein phosphatase-1C
"$T$1C#% as 'ell as mem$ers o" the Src "amily o" protein tyrosine
kinases "$T!s##
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,on-Receptor $rotein Tyrosine !inases
"$T!s#
There are numerous intracellular PTKs that are responsi$le "or
phosphorylating a !ariety o" intracellular proteins on tyrosine residues
"ollo'ing acti!ation o" cellular gro'th and proli"eration signals# There is
no' recogni*ed t'o distinct "amilies o" non-receptor PTKs# The archetypal
PTK "amily is related to the Src protein# The Src protein is a tyrosine
&inase "irst identi"ied as the trans"orming protein in Rous sarcoma !irus#
Su$se7uently% a cellular homolog 'as identi"ed as c-Src# Numerous proto-
oncogenes 'ere identi"ied as the trans"orming proteins carried $y
retro!iruses# The second "amily is related to the -anus kinase "-ak##
Most o" the proteins o" $oth "amilies o" non-receptor PTKs couple to
cellular receptors that lac& en*ymatic acti!ity themsel!es# This class o"
receptors includes all o" the cyto&ine receptors ,eg the interleu&in-: ,I>-:/
receptor/ as 'ell as the C-0 and C-? cell sur"ace glycoproteins o" T cells
and the T cell antigen receptor ,TCR/# This mode o" coupling receptors to
intracellular PTKs suggests a split "orm o" RTK#
4nother e)ample o" receptor-signaling through protein interaction in!ol!es
the insulin receptor ,IR/# This receptor has intrinsic tyrosine &inase acti!ity
$ut does not directly interact% "ollo'ing autophosphorylation% 'ith
en*ymatically acti!e proteins containing SH: domains ,e#g# PI-;K or P>C-
/# Instead% the principal IR su$strate is a protein termed IRS-8# IRS-8
contains se!eral moti"s that resem$le SH: $inding consensus sites "or the
catalytically acti!e su$unit o" PI-;K# These domains allo' comple)es to
"orm $et'een IRS-8 and PI-;K# This model suggests that IRS-8 acts as a
docking or adapter protein to couple the IR to SH: containing signaling
proteins#
4dditional adapter proteins ha!e $een identi"ied% the most commonly
occurring $eing a protein termed gro.th factor receptor-/inding protein
20 Gr/2#
4n e)ample o" an alteration in receptor acti!ity in response to association
'ith an intracellular PTK is the nicotinic acetylcholine receptor ,4ChR/#
These receptors comprise an ion channel consisting o" "our distinct
su$units ,% % % and /# The % % and su$units are tyrosine
phosphorylated in response to acetylcholine $inding 'hich leads to an
increase in the rate o" desensiti*ation to acetylcholine#
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Receptor Serine/Threonine !inases "RST!s#
The receptors "or the TG+- super"amily o" ligands ha!e intrinsic
serine/threonine &inase acti!ity# There are more than ;@ multi"unctional
proteins o" the TG+- super"amily 'hich also includes the acti!ins% inhi$ins
and the $one morphogenetic proteins ,MPs/# This super"amily o" proteins
can induce and/or inhi$it cellular proli"eration or di""erentiation and
regulate migration and adhesion o" !arious cell types# The signaling
path'ays utili*ed $y the TG+-% acti!in and MP receptors are di""erent
than those "or receptors 'ith intrinsic tyrosine &inase acti!ity or that
associate 'ith intracellular tyrosine &inases#
4t least 85 RSTKs ha!e $een isolated and can $e di!ided into :
su$"amilies identi"ied as the type I and type II receptors# >igands "irst $ind
to the type II receptors 'hich then leads to interaction 'ith the type I
receptors# Ahen the comple) $et'en ligand and the : receptor su$types
"orms% the type II receptor phosphorylates the type I receptor leading to
initiation o" the signaling cascade# Bne predominant e""ect o" TG+- is
regulation o" progression through the cell cycle# Bne nuclear protein
in!ol!ed in the responses o" cells to TG+- is the proto-oncogene% c-Myc
,Cmic&C/ 'hich directly a""ects the e)pression o" genes har$oring Myc-
$inding elements#
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,on-Receptor Serine/Threonine !inases
The are se!eral serine/threonine &inases that "unction in signal
transduction path'ays# The t'o more commonly &no'n are c%M$-
dependent protein kinase "$!%# and protein kinase C "$!C##
4dditional serine/threonine &inases important "or signal transduction are
the mitogen acti1ated protein kinases "M%$ kinases##
$rotein !inase C "$!C#
PKC 'as originally identi"ied as a serine/threonine &inase that 'as
ma)imally acti!e in the presence o" diacylglycerols ,-4G/ and calcium ion#
It is no' &no'n that there are at least ten proteins o" the PKC "amily# .ach
o" these en*ymes e)hi$its speci"ic patterns o" tissue e)pression and
acti!ation $y lipid and calcium# PKCs are in!ol!ed in the signal
transduction path'ays initiated $y certain hormones% gro'th "actors and
neurotransmitters# The phosphorylation o" !arious proteins% $y PKC% can
lead to either increased or decreased acti!ity# B" particular importance is
the phosphorylation o" the .G+ receptor $y PKC 'hich do'n-regulates
the tyrosine &inase acti!ity o" the receptor# This e""ecti!ely limits the length
o" the cellular responses initiated through the .G+ receptor#
M%$ !inases
M4P &inases 'ere identi"ied $y !irtue o" their acti!ation in response to
gro'th "actor stimulation o" cells in culture% hence the name mitogen
acti1ated protein kinases# M4P &inases are also called .RKs "or
e'tracellular-signal regulated kinases# Bn the $asis o" in vitro
su$strates the M4P &inases ha!e $een !ariously called microtu$ule
associated protein-: &inase ,M4P-: &inase/% myelin $asic protein &inase
,MP &inase/% ri$osomal SD protein &inase ,RSK-&inase( i#e# a &inase that
phosphorylates a &inase/ and .G+ receptor threonine &inase ,.RT
&inase/# 4ll o" these proteins ha!e similar $iochemical properties% immuno-
crossreacti!ities% amino acid se7uence and a$ility to in vitro phosphorylate
similar su$strates#
Ma)imal M4P &inase acti!ity re7uires that $oth tyrosine and threonine
residues are phosphorylated# This indicates that M4P &inases act as
s'itch &inases that transmits in"ormation o" increased intracellular tyrosine
phosphorylation to that o" serine/threonine phosphorylation# 4lthough M4P
&inase acti!ation 'as "irst o$ser!ed in response to acti!ation o" the .G+%
P-G+% NG+ and insulin receptors% other cellular stimuli such as T cell
acti!ation ,'hich signals through the >c& 2lick3 tyrosine &inase/% phor$ol
esters ,that "unction through acti!ation o" PKC/% throm$in% $om$esin and
$rady&inin ,that "unction through G-proteins/ as 'ell as N-methyl---
aspartate ,NM-4/ receptor acti!ation and electrical stimulation rapidly
induce tyrosine phosphorylation o" M4P &inases#
M4P &inases are% ho'e!er% not the direct su$strates "or RTKs nor receptor
associated tyrosine &inases $ut are in "act acti!ated $y an additional class
o" &inases termed M4P &inase &inases ,M4PK &inases/ and M4PK &inase
&inases ,M4PKK &inases/# Bne o" the M4PK &inases has $een identi"ied
as the proto-oncogenic serine/threonine &inase% Ra"# 9ltimate targets o"
the M4P &inases are se!eral transcriptional regulators e#g# serum
response "actor ,SR+/% and the proto-oncogenes +os% Myc and Eun as
'ell as mem$ers o" the steroid/thyroid hormone receptor super "amily o"
proteins#
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$hospholipases and $hospholipids in Signal
Transduction
Phospholipases and phospholipids are in!ol!ed in the processes o"
transmitting ligand-receptor induced signals "rom the plasma mem$rane to
intracellular proteins# The primary protein a""ected $y the acti!ation o"
phospholipases is PKC 'hich is ma)imally acti!e in the presence o"
calcium ion and -4G# The generation o" -4G occurs in response to
agonist acti!ation o" !arious phospholipases# The principal mediators o"
PKC acti!ity are receptors coupled to acti!ation o" phospholipase C-
,P>C-/# P>C- contains SH: domains that allo' it to interact 'ith tyrosine
phosphorylated RTKs# This allo's P>C- to $e intimately associated 'ith
the signal transduction comple)es o" the mem$rane as 'ell as mem$rane
phospholipids that are its su$strates# 4cti!ation o" P>C- leads primarily to
the hydrolysis o" mem$rane phosphatidylinositol $isphosphate ,PIP
:
/
leading to an increase in intracellular -4G and inositol trisphosphate ,IP
;
/#
The released IP
;
interacts 'ith intracellular mem$rane receptors leading
to an increased release o" stored calcium ions# Together% the increased
-4G and intracellular "ree calcium ion concentrations lead to increased
acti!ity o" PKC#
Recent e!idence indicates that phospholipases - and 4
:
,P>- and P>4
:
/
also are in!ol!ed in the sustained acti!ation o" PKC through their
hydrolysis o" mem$rane phosphatidylcholine ,PC/# P>- action on PC
leads to the release o" phosphatidic acid 'hich in turn is con!erted to -4G
$y a speci"ic phosphatidic acid phosphomonoesterase# P>4
:

hydroly*es PC to yield "ree "atty acids and lysoPC $oth o" 'hich ha!e
$een sho'n to potentiate the -4G mediated acti!ation o" PKC# B" medical
signi"icance is the a$ility o" phor/ol ester tumor promoters to acti!ate
PKC directly# This leads to ele!ated and unregulated acti!ation o" PKC
and the conse7uent disruption in normal cellular gro'th and proli"eration
control leading ultimately to neoplasia#
$hosphatidylinositol--!inase "$+-!#
PI-;K is tyrosine phosphorylated% and su$se7uently acti!ated% $y !arious
RTKs and receptor-associated PTKs# PI-;K is a heterodimeric protein
containing an ?1 &-a and 88@ &-a su$units# The p?1 su$unit contains
SH: domains that interact 'ith acti!ated receptors or other receptor-
associated PTKs and is itsel" su$se7uently tyrosine phosphorylated and
acti!ated# The ?1 &-a su$unit is non-catalytic% ho'e!er% it does contain a
domain homologous to GTPase acti!ating ,G4P/ proteins# It is the 88@
&-a su$unit that is en*ymatically acti!e# PI-;K% associates 'ith and is
acti!ated $y% the P-G+% .G+% insulin% IG+-8% HG+ and NG+ receptors# PI-
;K phosphorylates !arious phosphatidylinositols at the ; position o" the
inositol ring# This acti!ity generates additional su$strates "or P>C-
allo'ing a cascade o" -4G and IP; to $e generated $y a single acti!ated
RTK or other protein tyrosine &inases#
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G-$rotein Coupled Receptors
There are se!eral di""erent classi"ications o" receptors that couple signal
transduction to G-proteins# These classes o" receptor are termed G-
protein coupled receptors0 G$CRs# Aell o!er 8@@@ di""erent GPCRs
ha!e $een cloned% most $eing orphan receptors ha!ing no as yet
identi"ied ligand# Three di""erent classes o" GPCR are re!ie'ed(
1. GPCRs that modulate adenylate cyclase acti!ity# Bne class o"
adenylate cyclase modulating receptors acti!ate the en*yme
leading to the production o" c4MP as the second messenger#
Receptors o" this class include the -adrenergic% glucagon and
odorant molecule receptors# Increases in the production o" c4MP
leads to an increase in the acti!ity o" PK4 in the case o" -
adrenergic and glucagon receptors# In the case o" odorant molecule
receptors the increase in c4MP leads to the acti!ation o" ion
channels# In contrast to increased adenylate cyclase acti!ity% the -
type adrenergic receptors are coupled to inhi$itory G-proteins that
repress adenylate cyclase acti!ity upon receptor acti!ation#
2. GPCRs that acti!ate P>C- leading to hydrolysis o"
polyphosphoinositides ,e#g# PIP
:
/ generating the second
messengers% diacylglycerol ,-4G/ and inositoltrisphosphate ,IP
;
/#
This class o" receptors includes the angiotensin% $rady&inin and
!asopressin receptors#
. 4 no!el class o" GPCRs are the photoreceptors# This class is
coupled to a G-protein termed transducin that acti!ates a
phosphodiesterase 'hich leads to a decrease in the le!el o" cGMP#
The drop in cGMP then results in the closing o" a Na
F
/Ca
:F
channel
leading to hyperpolari*ation o" the cell# See the Role o" =itamin 4 in
=ision "or more details#
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G-$rotein Regulators
The acti!ity o" G-proteins 'ith respect to GTP hydrolysis is regulated $y a
"amily o" proteins termed GT$ase acti1ating proteins0 G%$s# The proto-
oncogenic protein% Ras% is a G-protein in!ol!ed in the genesis o"
numerous "orms o" cancer ,'hen the protein sustains speci"ic mutations/#
B" particular clinical signi"icance is the "act that oncogenic acti!ation o"
Ras occurs 'ith higher "re7uency than any other gene in the de!elopment
o" colo-rectal cancers# Regulation o" Ras GTPase acti!ity is controlled $y
rasG%$#
There are se!eral other G4P proteins $esides rasG4P that are important
in signal transduction# There are t'o clinically important proteins o" the
G4P "amily o" proteins# Bne is the gene product o" the neuro"i$romatosis
type-8 ,N+8/ suscepti$ility locus# The N+8 gene is a tumor suppressor
gene and the protein encoded is called neurofi/romin# The second is the
protein encoded $y the CR locus ,/reak point cluster region gene/#
The CR locus is rearranged in the PhiladelphiaF chromosome ,Ph
F
/
o$ser!ed 'ith high "re7uency in chronic myelogenous leu&emias ,CM>s/
and acute lymphocytic leu&emias ,4>>s/#
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+ntracellular )ormone Receptors
Hormone receptors are proteins that e""ecti!ely $ypass all o" the signal
transduction path'ays descri$ed thus "ar $y residing 'ithin the cytoplasm#
4dditionally% all o" the hormone receptors are $i-"unctional# They are
capa$le o" $inding hormone as 'ell as directly acti!ating gene
transcription#
The steroid/thyroid hormone receptor super"amily ,e#g# glucocorticoid%
!itamin -% retinoic acid and thyroid hormone receptors/ is a class o"
proteins that reside in the cytoplasm and $ind the lipophilic steroid/thyroid
hormones# These hormones are capa$le o" "reely penetrating the
hydropho$ic plasma mem$rane# 9pon $inding ligand the hormone-
receptor comple) translocates to the nucleus and $ind to speci"ic -N4
se7uences termed hormone response elements ")R&s## The $inding o"
the comple) to an HR. results in altered transcription rates o" the
associated gene#
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$hosphatases in Signal Transduction
Su$stantial e!idence lin&s $oth tyrosine and serine/threonine
phosphorylation 'ith increased cellular gro'th% proli"eration and
di""erentiation# Remo!al o" the incorporated phosphates must $e a
necessary e!ent in order to turn o"" the proli"erati!e signals# This suggests
that phosphatases may "unction as anti-oncogenes or gro'th suppressor
genes# The loss o" a "unctional phosphatase in!ol!ed in regulating gro'th
promoting signals could lead to neoplasia# Ho'e!er% e)amples are &no'n
'here dephosphorylation is re7uired "or promotion o" cell gro'th# This is
particularly true o" speciali*ed &inases that are directly in!ol!ed in
regulating cell cycle progression# There"ore% it is di""icult to en!ision all
phosphatases as $eing tumor suppressor genes#
There are t'o $road classes o" protein tyrosine phosphatases "$T$s##
Bne class are transmem$rane en*ymes 'hich contain the phosphatase
acti!ity domain in the intracellular portion o" the protein# The other are
intracellularly locali*ed en*ymes# The "irst transmem$rane PTP
characteri*ed 'as the leukocyte common antigen protein0 C234# This
protein 'as sho'n to ha!e homology to the intracellular PTP% PTP8#
There are at least si) su$-classes o" the transmem$rane PTPs#
The clearest studies o" a role "or transmem$rane PTPs in signal
transduction ha!e in!ol!ed the C-01 protein# These studies ha!e sho'n
that C-01 is in!ol!ed in the regulation o" the tyrosine &inase acti!ity o" lc&
in T cells# 4s indicated a$o!e >c& is associated 'ith T cell antigens C-0
and C-? generating a split-RTK in!ol!ed in T cell acti!ation# It is
suspected that C-01 dephosphorylates a regulatory tyrosine
phosphorylation site in the C-terminus o" >c&% there$y% increasing the
acti!ity o" >c& to'ards its su$strate,s/#
The second class o" PTPs are the intracellular proteins# The C-terminal
residues o" most i" not all intracellular PTPs are !ery hydropho$ic and
suggest these sites are mem$rane attachment domains o" these proteins#
Bne role o" intracellular PTPs is in the maturation o" Xenopus oocytes in
response to hormone# B!er e)pression o" PTP-8 in oocytes resulted in a
mar&ed retardation in the rate o" insulin- and progesterone-induced
maturation# These results suggest a role "or PTP-8 in countering the
signals leading to cellular acti!ation#
The a$o!e o$ser!ation as 'ell as se!eral others ha!e demonstrated a lin&
$et'een insulin "unction and PTP-8# PTP-8 directly interacts 'ith the
insulin receptor and remo!es the tyrosine phosphates incorporated $y
autophosphorylation in response to insulin $inding% there$y% negati!ely
a""ecting the acti!ity o" the insulin receptor# Recently the PTP-8 gene 'as
disrupted in mice $y targeted deletion# Mice lac&ing a "unctional PTP-8
gene e)hi$it increased insulin sensiti!ity as 'ell as resistance to o$esity
induced $y a high "at diet#
4s 'ith the transmem$rane PTPs little is &no'n a$out the regulation o"
the acti!ity o" the intracellular PTPs#
T'o intracellular PTPs ,PTP-8C and PTP-8-/ ha!e $een sho'n to contain
SH: domains# These SH: domains allo' these PTPs to directly interact
'ith tyrosine phosphorylated RTKs and PTKs% there$y% dephosphorylating
tyrosines in these proteins# +ollo'ing receptor stimulation o" signal
transduction e!ents% the SH: containing PTPs are directed to se!eral o"
the RTKs and/or PTKs 'ith the net e""ect $eing a termination o" the
signaling e!ents $y tyrosine dephosphorylation
Bther phosphatases that recogni*e serine and/or threonine
phosphorylated proteins also e)ist in cells# These are re"erred to as
protein serine phosphatases "$S$s## 4t least 81 distinct PSPs ha!e
$een identi"ied# The type :4 PSPs e)hi$it selecti!e su$strate speci"icity
to'ards PKC phosphorylated proteins< in particular serine and threonine
phosphorylated receptors# Type :4 PSPs are more e""ecti!e than other
PSPs in dephosphorylating RSKs% proteins that are in!ol!ed in signaling
cascades $y phosphorylating ri$osomal SD protein ,see a$o!e/# Ho'e!er%
a type 8 PSP is re7uired to dephosphorylate SD itsel"#
The type :4 PSPs ha!e : su$units ,a regulatory and a catalytic/ $oth o"
'hich can associate 'ith one o" the tumor antigens o" the -N4 tumor
!irus% polyoma# Trans"ormation $y -N4 tumor !iruses such as polyoma
appears to $e mediated $y the "ormation o" a signal transduction unit
consisting o" a !irally encoded T antigen and se!eral host encoded
proteins# Se!eral host proteins are tyrosine &inases o" the src "amily#
Polyoma middle T antigen also can $ind to PI-;K# The association o" type
:4 PSPs in these comple)es may lead to dephosphorylation o" regulatory
serine/threonine phosphorylated sites resulting in increased signal
transduction and su$se7uent cellular proli"eration#
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Return to Medical iochemistry Page
Michael W. King, Ph.D / I !chool o" Medicine /
m#ing$medicine.indstate.edu
>ast modi"ied( Tuesday0 12-%ug-255 2565467 &ST