Posted by: Dan | May 21, 2007

Integrin Recycling and Directional Persistence in Cell Migration

While I get the response ready for reviewers of the paper that I’m trying to get published, which is on persistent cell migration in adherent cells, there’s another paper on just that topic recently that caught my attention. A Scotish lab has a paper in JCB on how {alpha}v{beta}3 and {alpha}5{beta}1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration.

White and colleagues focused on the transport mechanisms mediated by Protein Kinase D-1 (PKD1), and pertaining to focal adhesion dynamics. They note well that studying vesicular transport by PKD1 has been plagued by the difficulty that most PKD1 mutants get stuck in the Golgi, obscuring other functions of this protein. Here, they uncovered and examined a mutant (Ser916 to Ala) that does not get stuck in the Golgi, and also has a function in membrane recycling.

Fig9

PKD1-S916A mutants appear to be defective in returning {alpha}v{beta}3 integrin receptors to the cell surface. And, while kinase-dead PKD1 and RNAi reduce both speed and directionality in migration, S916A selectively blocks directionality. White et al. conclude that integrin recycling is necessary for persistent migration, and this jibes well with the treadmilling model of the focal adhesions and cytoskeleton at the leading edge of migrating cells.

Also, the authors found that persistence in S916A mutants can be rescued by downregulation of the {alpha}5{beta}1-ROCK-cofilin pathway, such that {alpha}5{beta}1 can still facilitate focal adhesion turnover. This alternate integrin receptor is essentially redundant for motility on fibronectin/vitronectin, as is known, but it also resembles something described as transdominant-inhibition, where alternative integrin receptors may inhibit one another’s activity.

But perhaps more interesting than the integrin receptor story in this paper, is the ROCK-cofilin story, which is emphasized as a central pathway in promoting randomness in motility.

  • White DP, Caswell PT, Norman JC. {alpha}v{beta}3 and {alpha}5{beta}1 integrin recycling pathways dictate downstream Rho kinase signaling to regulate persistent cell migration.
    J Cell Biol. 2007 May 7;177(3):515-25. Pubmed
  • Vial E, Sahai E, Marshall CJ. ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility.
    Cancer Cell. 2003 Jul;4(1):67-79. Pubmed

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