1. Integrin Mechano-signaling

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

3. Outline Characteristics of Integrins Outside-in signaling
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 Outside-in signaling
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)17

18. Huveneers (2009)

19. Huveneers (2009)

20. Guarino (2010)

21. Guarino (2010)

22. Guarino (2010)

23. Outline Characteristics of Integrins Outside-in signaling
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 Outside-in signaling
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:
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:
Huveneers, S. & Danen, E.H. (2009). Adhesion signaling – crosstalk between integrins, Src and Rho. J Cell Sci. 122:
Assoian, R.K., Klein E.A. (2008). Growth control by intracellular tension and extracellular stiffness. Trends Cell Biol. 18(7):
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:
Puklin-Faucher, E., & Sheetz, M.P. (2009). The mechanical integrin cycle. J Cell Sci. 122:
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:
Baker, E.L., and Zaman, M.H., “The biomechanical integrin.” J Biomech January 5; 43(1): 38
Qin, J., Vinogradova, O., and Plow E.F. “Integrin bidirectional signaling: A Molecular View.” PLoS Biol June; 2(6): e169
Shattil et al. (2004). Integrins: dynamic scaffolds for adhesion and signaling in platelets.” Blood. 104:
Moore et al. (2010). “Stretch Proteins on Stretchy Substrates: The important elements of integrin-medicated rigidity sensing.” Dev Cell. 19:
Schedin & Keely (2010). “Mammary Gland ECM Remodeling, Stiffness and mechanosignaling in normal development and tumor progressio.” Cold Spring Harbor Perspectives in Biology.