Posted by: Dan | May 30, 2006

Cell rigidity and protein recruitment

Molecular Biology of the Cell‘s June issue has a paper from Michael Sheetz’s lab at Columbia, describing the Fibronectin Rigidity Response through Fyn and p130Cas Recruitment to the Leading Edge. Although I haven’t to-date heard much about this response, Kostic and Sheetz describe the “matrix rigidity response” in much the same way as Donald Ingber’s Tensegrity Model in cellular and tissue structural modeling, saying that “the generation of force on rigid matrix contacts causes reinforcement of the integrin-cytoskeleton linkages through recruitment of focal adhesion proteins, increased cell adhesion.

Ingber’s Tensegrity model describes how a “simple mechanical model of cell structure based on tensegrity architecture can help to explain how cell shape, movement and cytoskeletal mechanics are controlled, as well as how cells sense and respond to mechanical forces” by examining cell structure, biochemical signaling and mechanoregulation. Both Sheetz and Ingber seem to be describing what Ingber calls mechanotransduction – how cells convert mechanical signals into biochemical responses. Among the known components at the mechanical-biochemical interface are integrin-cytoskeleton connections at focal adhesions, contractile myosin motors, and cytoskeleton-reorganizing Rho-family GTPases.

In the MBC paper, Kostic and Sheetz focus in on integrin-mediated generation of force through matrix adhesions at the leading edge of migrating cells, through AvB3 integrin and receptor-like protein tyrosine phosphatase alpha (RPTPa). Here, they follow the signal transduction cascade downstream to Src family kinases (SFKs), on the basis that RPTPa(-/-) cells and Src/Fyn/Yes(-/-) cells (the three SFKs) exhibit similar spreading behavior, and that RPTPa activates SFKs through dephosphorylation of their C-terminal negatively regulatory phosphotyrosines.
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Their findings, as documented in the paper, suggest that Fyn (and not Src or Yes) is activated by RPTPa upon rigid fibronectin attachment, in turn phosphorylating p130Cas. Further, they find that Fyn’s palmitoylation site is required for recruitment of Fyn to early focal contacts, and that this site is absent in Src and Yes. As a result, Fyn’s signaling through p130Cas is both force- and position-dependent.

While this isn’t startling news – the importance of SFKs and p130Cas in focal adhesion dynamics has been known for ten years or so – it’s a nice example of the step-by-step progress that’s being made to delineate the biochemical mechanisms involved in focal adhesion assembly and disassembly, and their role in generating tension and motility.

References:

  • Adhesion assembly, disassembly and turnover in migrating cells — over and over and over again. Webb DJ, Parsons JT, Horwitz AF. Nat Cell Biol. 2002 Apr; 4(4):E97-100. Pubmed
  • Cell tension, matrix mechanics, and cancer development. Huang S, Ingber DE. Cancer Cell. 2005 Sep; 8(3):175-6. Pubmed
  • Fibronectin Rigidity Response through Fyn and p130Cas Recruitment to the Leading Edge. Kostic A, Sheetz MP. Mol Biol Cell. 2006 Jun; 17(6):2684-2695. Pubmed
  • Local force and geometry sensing regulate cell functions. Vogel V, Sheetz M. Nat Rev Mol Cell Biol. 2006 Apr; 7(4):265-75. Pubmed

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