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RESEARCH PAPER
1 Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Division of Basic Science, Seattle, Washington 98109, USA; 2 MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK
The tumor suppressor p27Kip1 is an inhibitor of cyclin/cyclin-dependent kinase (CDK) complexes and plays a crucial role in cell cycle regulation. However, p27Kip1 also has cell cycle-independent functions. Indeed, we find that p27Kip1 regulates cell migration, as p27Kip1-null fibroblasts exhibit a dramatic decrease in motility compared with wild-type cells. The regulation of motility by p27Kip1 is independent of its cell-cycle regulatory functions, as re-expression of both wild-type p27Kip1 and a mutant p27Kip1 (p27CK–) that cannot bind to cyclins and CDKs rescues migration of p27–/– cells. p27–/– cells have increased numbers of actin stress fibers and focal adhesions. This is reminiscent of cells in which the Rho pathway is activated. Indeed, active RhoA levels were increased in cells lacking p27Kip1. Moreover, inhibition of ROCK, a downstream effector of Rho, was able to rescue the migration defect of p27–/– cells in response to growth factors. Finally, we found that p27Kip1 binds to RhoA, thereby inhibiting RhoA activation by interfering with the interaction between RhoA and its activators, the guanine–nucleotide exchange factors (GEFs). Together, the data suggest a novel role for p27Kip1 in regulating cell migration via modulation of the Rho pathway.
[Keywords: p27Kip1; Rho; migration; actin stress fibers; Ras; ROCK]
Received January 13, 2004; revised version accepted March 10, 2004.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1185504.
E-MAIL jroberts{at}fhcrc.org; FAX.
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