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Tropomyosin and tyrosine kinases in mechanics of cancer

Michael Patrick Sheetz

1 Collaborator(s)

Funding source

National Institutes of Health (NIH)
The major goal of our lab is to understand the molecular pathways involved in rigidity and force sensing at cell-matrix adhesions. In this grant we will explore how these pathways are altered in cancers related to depletion of tropomyosin and modifications of tyrosine kinases. Cancer cells typically show anchorage independence of growth and the cytoskeletal protein, tropomyosin (Tm), is depleted in many cancers. Further, restoration of normal Tm1 expression reverses the transformed phenotype. Recently our lab has shown that cell rigidity sensing depends upon local contraction units that displace matrix by 50-70nm and if a threshold force is exceeded rapidly, then rigid adhesions form. Local contraction units resemble muscle sarcomeres in size (~2 •, function, and composition (actin, myosin II, alpha-actinin, tropomodulin and tropomyosin). After knockdown of Tm1, the local contractions are dramatically altered and the cells no longer sense the rigidity of fibronectin-coated substrates. Similarly, the knockdown of tyrosine kinases alters both rigidity sensing and the pattern of contractions that are measured from displacements of 500nm diameter PDMS pillars. We propose now to follow the time course of force dependence and the concentration and dissipation of adhesion and contractile proteins at the pillars. This will tell us the order ofbinding and provide clues about the molecular steps involved in the cycles of contraction and release. We will then address the question of how the tyrosine kinases involved in rigidity sensing (AXL, ROR2 and EGF) interplay with the early adhesion complexes as a function of the force on the complexes. Since tropomyosin inhibits transformation and tumor growth, we will determine how tropomyosin depletion alters the pattern of adhesion maturation on soft surfaces that enables transformation. Thus, we will be able to better understand the mechanochemical basis of transformation.

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