Editors' ChoiceCell Biology

Small but Strong

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Science Signaling  02 Jun 2009:
Vol. 2, Issue 73, pp. ec187
DOI: 10.1126/scisignal.273ec187

The sites at which integrins mediate the interaction of a cell with the substrate are focal contacts (FCs); these begin as nascent adhesion sites that transmit stronger tension forces and may mature into focal complexes (FXs) and eventually into the largest molecular complex, called the focal adhesion (FA), which transmits weaker forces. FCs are dynamic structures, and cells must regulate their formation and disassembly in order to migrate or withstand forces. Nudel is a protein that functions in microtubule-based processes and participates in cell migration by promoting the activity of the guanosine triphosphatase Cdc42. Shan et al. provide evidence that nudel also contributes to cell migration by interacting with paxillin, a FC-associated protein that interacts directly with integrins. In nudel-depleted cells, forced expression of active Cdc42 or Rac1 failed to completely restore cell motility and cell spreading, which appeared to be due to decreased formation of nascent adhesion sites. Nudel-depleted cells exhibited a collapse of the cell periphery associated with large FAs and stress fibers at the periphery. Nudel interacted with paxillin, based on coimmunoprecipitation experiments of tagged proteins and in vitro assays with purified proteins. In cells, cross-correlation microscopy revealed that nudel and paxillin colocalized at the leading edge of the cell, but not right behind the leading edge. Expression of a fusion protein of nudel to paxillin reduced FA motility (FAs typically exhibit centripetal movement) and enhanced the adhesion of cells exposed to shear force, suggesting that nudel promotes the strength of adhesion. Nudel was not detected in FXs or FAs, which exhibit weaker adhesion strength. Overexpression of focal adhesion kinase (FAK) abolished the coimmunoprecipitation of tagged nudel and paxillin. This required the FAT domain, through which FAK binds paxillin, but did not require kinase activity. Depletion of FAK with RNAi promoted the interaction between paxillin and nudel. Overexpression of FAK mutants in the “open” or active conformation that also contained a functional FAT domain promoted the formation of polygonal cells, instead of the typical round cells, and was associated with loss of FXs. The authors propose that the association of nudel with paxillin strengthens nascent adhesions to promote stable membrane protrusions at the leading edge and that the interaction of paxillin with FAK at FAs facilitates retraction of the trailing edge.

Y. Shan, L. Yu, Y. Li, Y. Pan, Q. Zhang, F. Wang, J. Chen, X. Zhu, Nudel and FAK as antagonizing strength modulators of nascent adhesions through paxillin. PLoS Biol. 7, e1000116 (2009). [Online Journal]

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