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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

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Presentation Transcript
outline
Outline
  • Characteristics of Integrins
    • Roles
    • Structure
    • Bidirectionality of signaling
    • Cytoplasmic Activators
  • Outside-in signaling
    • Cellular adhesion
  • Inside-out signaling
    • Platelets
  • Roles in cancer
outline3
Outline

Characteristics of Integrins

Roles

Structure

Bidirectionality of signaling

Cytoplasmic Activators

Outside-in signaling

Cellular adhesion

Inside-out signaling

Platelets

Roles in cancer

slide4

RECALL

Ben-Shlomo et al (2003)

roles of integrins
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
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
Conformational changes
  • Regulate binding affinity
  • May be dependent on force
  • Bent (“inactive”) conformation can sometimes still bind ligand
integrin signals bidirectionally
Integrin signals bidirectionally

NATURE REVIEWS | MOLECULAR CELL BIOLOGY

Shattil et al (2010)

clustering
Clustering
  • heterodimers → hetero-oligomers
  • Caused by inside-out signals
  • Important for triggering outside-in signaling
  • Influences the mechanotransduction of integrins
clustering11
Clustering

Qin et al (2004)

cytoplasmic activators talins
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)

outline14
Outline

Characteristics of Integrins

Structure

Bidirectionality of signaling

Cytoplasmic Activators

Outside-in signaling

Cellular adhesion

Inside-out signaling

Platelets

Roles in cancer

outside in signaling
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
outline23
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
Inside-out signaling
  • Intracellular activator binds to β-integrin tail → conformational change.

Shattil et al (2004)

integrin signaling in platelets iib 3
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
outline27
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
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
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
the big picture on integrins
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
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.