Integrin Mechano-signaling

1. Integrin Mechano-signaling

2. Outline • Characteristics of Integrins • Roles • Structure • Bidirectionality of signaling • Cytoplasmic Activators • Outside-in signaling • Cellular adhesion • Inside-out signaling • Platelets • Roles in cancer

3. Outline Characteristics of Integrins Roles Structure Bidirectionality of signaling Cytoplasmic Activators Outside-in signaling Cellular adhesion Inside-out signaling Platelets Roles in cancer

4. RECALL Ben-Shlomo et al (2003)

5. Roles of Integrins • Mediate cell attachment to other cells or extracellular matrix (ECM) • Stabilize tissue structure • Bear stress and transmit force • Facilitate cell migration • Contribute to disease and cancer progression

6. Structure • Heterodimer • 24 canonical integrins in mammals • Formed from combos of 18 α-subunits and 8 β-subunits • Undergo conformational changes that influence ligand affinity Moser (2009)

7. Conformational changes • Regulate binding affinity • May be dependent on force • Bent (“inactive”) conformation can sometimes still bind ligand

8. Shattil et al (2010)

9. Integrin signals bidirectionally NATURE REVIEWS | MOLECULAR CELL BIOLOGY Shattil et al (2010)

10. Clustering • heterodimers → hetero-oligomers • Caused by inside-out signals • Important for triggering outside-in signaling • Influences the mechanotransduction of integrins

11. Clustering Qin et al (2004)

12. Cytoplasmic Activators: Talins • A cytoskeletal protein • Bind to β-subunit → Integrin activation • inside-out signaling • Link actin cytoskeleton to ECM via F-actin Moser (2009), Shattil (2009)

13. Wang et al (2009)

14. Outline Characteristics of Integrins Structure Bidirectionality of signaling Cytoplasmic Activators Outside-in signaling Cellular adhesion Inside-out signaling Platelets Roles in cancer

15. Guarino (2010)

16. Outside-in signaling • Cells detect stiffness of environment • Stiffness is detected by integrins • Remodeling of cytoskeleton is induced • Cell is structurally protected from external mechanical stress

17. Puklin-Faucher & Sheetz (2009)

18. Huveneers (2009)

19. Huveneers (2009)

20. Guarino (2010)

21. Guarino (2010)

22. Guarino (2010)

23. Outline Characteristics of Integrins Structure Bidirectionality of signaling Cytoplasmic Activators Outside-in signaling Cellular adhesion Inside-out signaling Platelets Roles in cancer

24. Inside-out signaling • Intracellular activator binds to β-integrin tail → conformational change. Shattil et al (2004)

25. Deadbolt model of I-O Activation Shattil et al (2004)

26. Integrin signaling in Platelets: αIIbβ3 • A major platelet integrin • Required for platelet interxns with plasma proteins and ECM → adhesion and aggregation • Aggregation is controled by αIIbβ3 clustering • Disruptions can lead to inappropriate blood clotting or profuse bleeding

27. Outline Characteristics of Integrins Structure Bidirectionality of signaling Cytoplasmic Activators Outside-in signaling Cellular adhesion Inside-out signaling Platelets Roles in cancer

28. Integrins and Cancer: rigidity sensing • α5β1 integrins support higher matrix forces than less stable integrins • Parameters that determine rigidities a cell can sense via integrins: • Strength of integrin binding to EX ligands • Force and speed of cell retraction • Sensitivity of other mechanosensors

29. Integrins and cancer: Breast tissue • Mammary cells in a stiff matrix are more proliferative and have enhanced migration • Mammary cells in compliant matrices have better growth control • Tissue stiffness has been used to detect cancer • Paper for next week

30. On Monday:

31. The Big Picture on Integrins • Are adhesion molecules that connect the ECM to the cytoskeleton (and nucleus!) • Signal from the outside-in and from the inside-out • Different kinds of integrins have different main roles • Sense forces in their environment and mediate the movement of cells • Depend on conformation and clustering for their activity • Promote tumor proliferation when their mechanosignaling is perturbed

32. References • Shattil et al. (2010).The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol. 11: 288-300 • Caswel, P.T., Vadrevu, S., and Norman, J.C. (2009). Integrins: amsters and slaves of endocytic transport. • Guarino, M. (2010). Src signaling in cancer invasion. J Cell Physio. 243: 14-26 • Moser et al. (2009). The tail of integrins, talin, and kindlins. Science. 324: 895-899 • Huveneers, S. & Danen, E.H. (2009). Adhesion signaling – crosstalk between integrins, Src and Rho. J Cell Sci. 122: 1059-1069 • Assoian, R.K., Klein E.A. (2008). Growth control by intracellular tension and extracellular stiffness. Trends Cell Biol. 18(7): 347-352 • Caswell, P.T., & Norman, J.C. (2006). Integrin Trafficking and the Control of Cell Migration. Traffic. 7: 14-21 • Caswell, P.T., Suryakiran, V. & Norman, J.C. (2009). Integrins: masters and slaves of endocytic transport. Nature Rev. Mol. Cell Biol. 10: 843-853. • Puklin-Faucher, E., & Sheetz, M.P. (2009). The mechanical integrin cycle. J Cell Sci. 122: 179-186. • Wang, N., Tytell, J.D., Ingber, D.E. (2009). Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat Rev. Mol. Cell. Biol 10: 75-82 • Huveneers, S., and Danen, E.H. (2009). “Adhesion signaling – crosstalk between integrins Src and Rho.” J Cell Sci. 122: 1059-1069 • Baker, E.L., and Zaman, M.H., “The biomechanical integrin.” J Biomech. 2010 January 5; 43(1): 38 • Qin, J., Vinogradova, O., and Plow E.F. “Integrin bidirectional signaling: A Molecular View.” PLoS Biol. 2004 June; 2(6): e169 • Shattil et al. (2004). Integrins: dynamic scaffolds for adhesion and signaling in platelets.” Blood. 104: 1606-1615. • Moore et al. (2010). “Stretch Proteins on Stretchy Substrates: The important elements of integrin-medicated rigidity sensing.” Dev Cell. 19: 194-206 • Schedin & Keely (2010). “Mammary Gland ECM Remodeling, Stiffness and mechanosignaling in normal development and tumor progressio.” Cold Spring Harbor Perspectives in Biology.