Integrin Mechano-signaling

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

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

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

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 Outside-in signaling 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) 17

Huveneers (2009)

Huveneers (2009)

Guarino (2010)

Guarino (2010)

Guarino (2010)

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

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

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

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 Outside-in signaling 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

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.