WELCOME

Seminar By : V.SIDDHARTHA REDDY Topic : INTEGRINS Date : Feb-26-2011 Venue : Aurora P.G College

WHAT WE ARE GOING TO LEARN

What Are INTEGRINS ? How They Look Like(Structural Features)? How They Get Activated? Their number and classification? Are they really useful/useless?

WHAT ARE INTEGRINS ?

super family of cell adhesion receptors that bind to extracellular matrix ligands , cell-surface ligands ,and soluble ligands Found In : Mammals
Chicken Zebra fish Lower Eukaryotes *Inside out / out side in signaling

How They Look Like (Structural Features)?

 90 kDa to 160 kDa. N-terminal -extracellular side/C-terminalinside & sub-units are non homologous. Sequence identity among subunits- 30% / subunits-45%.(gene duplication evolution) Humans: their genes located on various chromosomes. Studies on Integrin genes-derived from common ancestral gene by gene duplication.

I-Domain,(interaction/insertion) I-like domain *Serves as RGD domain binding sites *RGD binding motif(asp-gly-asp).

Motomu Shimaoka et al 2002. 31:485-516.

Annu. Rev. Biophys. Biomol. Struct.

Their number and classification?

Drosophila: 5+1-5integrins C.elegans:

2+1-2integrins
Humans:

18 +8 24integrins 4/5: families

ntegrin Binding Specificities

NTEGRIN LIGAND DISTRIBUTION 51 Fibronectin Ubiquitous 61 Laminin Ubiquitous 71 Laminin Muscle L2 (LFA-1) Ig superfamily White blood cells ICAM-1 23 Fibrinogen Plaelets 64 Laminin Epithelial hemidesmosomes

1 subunits 2 subunits

Partner with at least 12 subunits WBC. Cell-cell adhesion. Ig superfam

Cell Junction
1. Tight (Occluding) Junctions

Function
Seals neighboring cells together in an epithelial sheet to prevent leakage of molecules between them

2. Anchoring Junctions Adherens Junction Focal Adhesion Desmosome Hemidesmosome Joins an actin bundle in one cell to an actin bundle in a neighboring cell Attaches actin filaments in a cell to extracellular matrix Spot weld that anchors the intermediate filaments in one cell to those in a neighboring cell
Anchors intermediate filaments in a cell to the basal lamina or underlying extracellular matrix

3. Communicating Junctions Gap Junction Chemical Synapse

Cell-cell junction which allows the passage of small water-soluble ions and molecules & electrical signals

Facilitates a type of

Focal Contacts
Integrins perform their work by focal contacts. Link extracellular matrix to actin filaments Allows cells to hang on to surroundings Bind to actin indirectly via anchor proteins Actin Vinculin

Lamellapodia Focal Contacts Movie 3-GFP JCB 155: 1319, 2001.

How They Get Activated?

m act ust b e iva ord ted i bi n e r t o n dt o E C t he M

Talin

Rap-mediated integrin activation.

Contd..next slide

Contnd..

Rap can activate(straightening)/inactivate(clu stering) towards the stimuli(agonistic/antagonistic). Rap=Ras Total Integrin Affinty: no.of active vs inactive forms.

Are they really useful/useless?

(Yep!! they are not useless like us, they perform various functions.)

Cell mobility/wound healing. cell signaling(growth and development). Leukocyte migration to the site of inflammation.

How can integrins affect cell motility?

The integrins can only bind to their binding partners when there is a minimum number of integrins present at specific places known as focal contacts. The affinity of integrins for their ligands is not very strong. Therefore, to form effective cell-to-cell or cell-to-extracellular matrix contacts, several integrins must be localized at the focal contact. Accordingly, when the integrins are diffusely distributed over the cell surface, no strong adhesion will be present. The low affinity of integrins for their ligands is necessary to prevent irreversible binding of cells, which would result in a lack of motility. By making and breaking focal contacts, a cell can actually move through its environment.

leukocyte migration
Selectins Integrins

Up-regulation of adhesion molecules on endothelial cells is induced by an array of inflammatory mediators such as TNF, IL-1, histamine and others produced by tissue resident inflammatory cells.

Integrins in epidermal cells during wound healing

Integrins enable epithelial cells to migrate during wound closure. In normal epidermis, integrins alpha-2 beta-1 and alpha-3 beta-1 are involved in cell-to-cell contacts. This means that they cause epidermal cells to stick to each other. During wound healing, migrating epithelial cells express new type of integrin,such as integrin alpha-5beta 1. This integrin is not present in normal unwounded epidermis. The appearance of integrin alpha-5 beta-1 starts shortly after wounding and it lasts only for a short duration.

51 For migr atio n

Normal: 21 31 (for cellcell contact)

(64)

 After a while, migrating epidermal cells start dividing and proliferating in order to make epidermal cell sheets and cover the wound area. This process is called re-epithelialization. At the same time, the epidermal cells start producing some of the components of basement membrane in order to stabilize the structure of newly-formed epidermis. The fusion of moving epidermal sheets is associated with the production of a new integrin, called alpha-v beta-6. integrin alpha-v beta-6 is involved in reconstruction of the new basement membrane.

 After reepithelialisation: Late production of v6(when cell migration stopped)from epithelial cells v6 activates transforming growth factor(TGF)-involved in *healing*sends signal to epidermal cells to stop dividing when their no.is sufficient(*scar formation regulation )

Extracellular Signalling
signaling molecules are released by signaling cells the signal is called the ligand the ligand binds to its specific receptor on a target cell this ligand-receptor interaction induces a conformational or shape-change in the receptor produces a specific response - called the cellular response can include a vast array of compounds
e.g. small amino acid derivatives, small peptides, proteins

Cell-to-cell communication by extracellular signaling usually involves six steps

(1) synthesis of the signaling molecule by the signaling cell (2) release of the signaling molecule by the signaling cell (3) transport of the signal to the target cell (4) detection of the signal by a specific receptor protein receptor-ligand specificity (5) a change in cellular metabolism, function, or development = cellular response
triggered by the receptor-ligand complex specific to the ligand-receptor complex

(6) removal of the signal, which usually terminates the cellular response degredation of ligand