Integrin Mechano-signaling

Outline

• Characteristics of Integrins– Roles– Structure– Bidirectionality of signaling– Cytoplasmic Activators

• Outside-in signaling– Cellular adhesion

• Inside-out signaling– Platelets

• Roles in cancer

Outline

• Characteristics of Integrins– Roles– Structure– Bidirectionality of signaling– Cytoplasmic Activators

• Outside-in signaling– Cellular adhesion

• Inside-out signaling– Platelets

• Roles in cancer

RECALL

Ben-Shlomo et al (2003)

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

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)

Conformational changes

• Regulate binding affinity

• May be dependent on force

• Bent (“inactive”) conformation can sometimes still bind ligand

Shattil et al (2010)

Integrin signals bidirectionally

Shattil et al (2010)NATURE REVIEWS | MOLECULAR CELL BIOLOGY

Clustering

• heterodimers → hetero-oligomers

• Caused by inside-out signals

• Important for triggering outside-in signaling

• Influences the mechanotransduction of integrins

Clustering

Qin et al (2004)

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)

Wang et al (2009)

Outline

• Characteristics of Integrins– Structure– Bidirectionality of signaling– Cytoplasmic Activators

• Outside-in signaling– Cellular adhesion

• Inside-out signaling– Platelets

• Roles in cancer

Guarino (2010)

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

Puklin-Faucher & Sheetz (2009)

Huveneers (2009)

Huveneers (2009)

Guarino (2010)

Guarino (2010)

Guarino (2010)

Outline

• Characteristics of Integrins– Structure– Bidirectionality of signaling– Cytoplasmic Activators

• Outside-in signaling– Cellular adhesion

• Inside-out signaling– Platelets

• Roles in cancer

Inside-out signaling

• Intracellular activator binds to β-integrin tail → conformational change.

Shattil et al (2004)

Shattil et al (2004)

Deadbolt model of I-O Activation

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

Outline

• Characteristics of Integrins– Structure– Bidirectionality of signaling– Cytoplasmic Activators

• Outside-in signaling– Cellular adhesion

• Inside-out signaling– Platelets

• Roles in cancer

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

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

On Monday:

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

References1. Shattil et al. (2010).The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol. 11: 288-300

2. Caswel, P.T., Vadrevu, S., and Norman, J.C. (2009). Integrins: amsters and slaves of endocytic transport.

3. Guarino, M. (2010). Src signaling in cancer invasion. J Cell Physio. 243: 14-26

4. Moser et al. (2009). The tail of integrins, talin, and kindlins. Science. 324: 895-899

5. Huveneers, S. & Danen, E.H. (2009). Adhesion signaling – crosstalk between integrins, Src and Rho. J Cell Sci. 122: 1059-1069

6. Assoian, R.K., Klein E.A. (2008). Growth control by intracellular tension and extracellular stiffness. Trends Cell Biol. 18(7): 347-352

7. Caswell, P.T., & Norman, J.C. (2006). Integrin Trafficking and the Control of Cell Migration. Traffic. 7: 14-21

8. Caswell, P.T., Suryakiran, V. & Norman, J.C. (2009). Integrins: masters and slaves of endocytic transport. Nature Rev. Mol. Cell Biol. 10: 843-853.

9. Puklin-Faucher, E., & Sheetz, M.P. (2009). The mechanical integrin cycle. J Cell Sci. 122: 179-186.

10. 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

11. Huveneers, S., and Danen, E.H. (2009). “Adhesion signaling – crosstalk between integrins Src and Rho.” J Cell Sci. 122: 1059-1069

12. Baker, E.L., and Zaman, M.H., “The biomechanical integrin.” J Biomech. 2010 January 5; 43(1): 38

13. Qin, J., Vinogradova, O., and Plow E.F. “Integrin bidirectional signaling: A Molecular View.” PLoS Biol. 2004 June; 2(6): e169

14. Shattil et al. (2004). Integrins: dynamic scaffolds for adhesion and signaling in platelets.” Blood. 104: 1606-1615.

15. Moore et al. (2010). “Stretch Proteins on Stretchy Substrates: The important elements of integrin-medicated rigidity sensing.” Dev Cell. 19: 194-206

16. Schedin & Keely (2010). “Mammary Gland ECM Remodeling, Stiffness and mechanosignaling in normal development and tumor progressio.” Cold Spring Harbor Perspectives in Biology.