1. Integrin signalling
Vytášek 2009

2. Extracellular matrix (ECM)
Network of macromolecules (proteins, glycoproteins, proteoglycans and polysaccharides)
Provides mechanical support for cells
Influences the behavior and differentiation of cells which are in contact with it
The main receptors of cells, mediating the interaction of cells with ECM, are known as integrins

3. Integrins
Necessary component of all Metazoans (from sponges to humans)
Any member of the large family of transmembrane proteins that acts as receptor for adhesion molecules of extracellular matrix
It plays a role in the attachment of the cell to the ECM and to other cells, and in signal transduction between ECM and the cell. This transduction is signaling from ECM to the cell (outside-in signaling) as well as signaling from the cell to extracellular space (inside-out signaling)

4. Integrin
Transmembrane protein which extracellular part is receptor for adhesion molecules of extracellular matrix
Heterodimeric molecules in which the  and  subunits are noncovalently bonded
 subunit has four Ca2+ -binding domain on its extracellular part of polypeptide chain
 subunit bears a number of cysteine-rich domains on its extracellular part of polypeptide chain

6. Adhesive sequences in matrix proteins and their integrin receptor

7. Outside-in signaling
Occupation of receptor site of integrin by appropriate ECM component causes conformational changes
Rearrangements also occur in intracellular part of integrin molecule and cause subsequent interactions with intracellular signaling pathways (eg. activation cytoplasmatic TPK (FAK) and serine/threonine kinases , activation of small GTPases, induction of calcium transport or changes of phospholipid synthesis)

8. Outside-in signaling
Conformational alterations also influence integrin clustering which further modify interactions between cytoplasmatic domains of integrin
Cellular phenotypes are determined by this type of signaling; integrins serve for cells as mechanosensors transfering information about ECM into cell and then altering cytoskeleton

10. Focal adhesion kinase (FAK) Protein tyrosine kinase 2 (PTK2)
cytoplasmic protein non-receptor tyrosine kinase
concentrated in the focal adhesions
phosphorylated in response to integrin interaction
the first activation step is autophosphorylation at Tyr397 full activation is achieved after further phosphorylation (Src, Fyn)

12. Stages of integrin receptor
Low affinity receptor (cells are not activated)
High affinity receptor (activated cells)
High affinity receptor and clustering of integrin (high avidity activation)

13. Inside-out signaling
Principle of signaling is changing affinity of integrin receptor for ECM
Nonactivated cells with low affinity integrin receptor after activation bound their intracellular part of integrin with integrin activating complex. It leads to conformation change of integrin molecule including extracellular part
Conformation alternation change affinity of receptor part of integrin from low to high afinity and binding to ECM in greater extend

14. Integrin activation in hematopoietic cells
Typical example is activation of platelets
Platelet integrin is maintained in the inactive state with low affinity for its extracellular ligand – fibrinogen
After platelet stimulation integrin is rapidly activated to high affinity leading to fibrinogen binding
Clotting of blood

15. Activation in tissues
Adherent cells (eg. fibroblasts) must be attached to ECM in constant manner to maintain tissue integrity
Inside-out signaling of integrin is very important during tissue remodeling and repairing after tissue damage
Migration of cells is also regulated by this signalling

16. Summary
Integrins, commonly found in Metazoans, mediate attachment cells to extracellular matrix and to other cells
Outside-in integrin signaling (binding of ligand to extracellular domain of integrin) regulates processes as protein phosphorylation, proliferation, differentiation and apoptosis
Inside-out signaling is caused by changing of affinity of ligand binding domain due allosteric rearrengement after association of cytoplasmatic integrin complex with intracellular part of integrin molecule

17. Further informations
Goldfinger,L.E., Ginsberg,M.H. : Integrin signaling in Encyklopedia of Biological Chemistry Vol.2 (2004)
Trends Cell Biol 14(2004)
Schwartz, M.A. : The Force Is with Us. Science 323(2009)