integrin mechano-signaling
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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.