The MEK1 Scaffolding Protein MP1 Regulates Cell Spreading by Integrating PAK1 and Rho Signals

Abstract

How the extracellular signal-regulated kinase (ERK) cascade regulates diverse cellular functions, including cell proliferation, survival, and motility, in a context-dependent manner remains poorly understood. Compelling evidence indicates that scaffolding molecules function in yeast to channel specific signals through common components to appropriate targets. Although a number of putative ERK scaffolding proteins have been identified in mammalian systems, none has been linked to a specific biological response. Here we show that the putative scaffold protein MEK partner 1 (MP1) and its partner p14 regulate PAK1-dependent ERK activation during adhesion and cell spreading but are not required for ERK activation by platelet-derived growth factor. MP1 associates with active but not inactive PAK1 and controls PAK1 phosphorylation of MEK1. Our data further show that MP1, p14, and MEK1 serve to inhibit Rho/Rho kinase functions necessary for the turnover of adhesion structures and cell spreading and reveal a signal-channeling function for a MEK1/ERK scaffold in orchestrating cytoskeletal rearrangements important for cell motility.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grants RO1 GM068111 to A.D.C. and P20 RR18766 (project principal investigator, A.D.C.; overall prinicpal investigator, Stephen Lanier) and start-up funds provided by the Department of Pharmacology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center.

We are grateful to S. Alahari, G. Bokoch, M. Cobb, L. Huber, M. Marshall, J. T. Parsons, M. Weber, S. Weed, and R. Worthylake for plasmids and antisera. We thank Electa Park for providing recombinant PAK1 and Mirek Cygler and Michael Sacher for their kind gift of recombinant MP1/p14 complex. We thank Adel Tarcsafalvi, Dan Santos, and Tomas Vomastek (University of Virginia) and members of the Boulares, Catling, Lanier, and Wu laboratories (Louisiana State University Health Sciences Center) for helpful discussions.