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¹ Department of Microbiology and Genetics, Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, 1030 Vienna, Austria
² Institute of Molecular Biotechnology IMBA, Vienna Biocenter, A-1030 Vienna, Austria
³ Department of Social and Environmental Medicine, Graduate School of Medicine
⁴ Center for Advanced Science and Innovation, Osaka University, Osaka 565-0871, Japan
⁵ Institute of Molecular and Cell Biology, Singapore 138673, Singapore

Correspondence to Manuela Baccarini: manuela.baccarini{at}univie.ac.at

Raf kinases relay signals inducing proliferation, differentiation, and survival. The Raf-1 isoform has been extensively studied as the upstream kinase linking Ras activation to the MEK/ERK module. Recently, however, genetic experiments have shown that Raf-1 plays an essential role in counteracting apoptosis, and that it does so independently of its ability to activate MEK. By conditional gene ablation, we now show that Raf-1 is required for normal wound healing in vivo and for the migration of keratinocytes and fibroblasts in vitro. Raf-1–deficient cells show a symmetric, contracted appearance, characterized by cortical actin bundles and by a disordered vimentin cytoskeleton. These defects are due to the hyperactivity and incorrect localization of the Rho-effector Rok- to the plasma membrane. Raf-1 physically associates with Rok- in wild-type (WT) cells, and reintroduction of either WT or kinase-dead Raf-1 in knockout fibroblasts rescues their defects in shape and migration. Thus, Raf-1 plays an essential, kinase-independent function as a spatial regulator of Rho downstream signaling during migration.

K. Ehrenreiter, D. Piazzolla, and V. Velamoor contributed equally to this paper.

V. Velamoor's present address is Cold Spring Harbor Labs, Cold Spring Harbor, NY 11724.

Abbreviations used in this paper: KC, kinase-competent; KD, kinase-dead; KGM, keratinocyte growth medium; KO, knockout; MYPT1, regulatory subunit of the myosin light chain phosphatase; WT, wild-type.

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