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J. Biol. Chem. 279 (4): 2616-2622

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Stress-specific Activation Mechanisms for the "Cell Integrity" MAPK Pathway*

Jacob C. Harrison, Trevin R. Zyla, Elaine S. G. Bardes, , and Daniel J. Lew{ddagger}

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710

Abstract: Many environmental stresses trigger cellular responses by activating mitogen-activated protein kinase (MAPK) pathways. Once activated, these highly conserved protein kinase cascades can elicit cellular responses such as transcriptional activation of response genes, cytoskeletal rearrangement, and cell cycle arrest. The mechanism of pathway activation by environmental stresses is in most cases unknown. We have analyzed the activation of the budding yeast "cell integrity" MAPK pathway by heat shock, hypoosmotic shock, and actin perturbation, and we report that different stresses regulate this pathway at different steps. In no case can MAPK activation be explained by the prevailing view that stresses simply induce GTP loading of the Rho1p GTPase at the "top" of the pathway. Instead, our findings suggest that the stresses can modulate at least three distinct kinases acting between Rho1p and the MAPK. These findings suggest that stresses provide "lateral" inputs into this regulatory pathway, rather than operating in a linear "top-down" manner.

Received for publication June 10, 2003. Revision received November 7, 2003.

* This work was supported by National Institutes of Health NIGMS Grant GM53050 and a Leukemia and Lymphoma Society Scholar Award (to D. J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Box 3813, Duke University Medical Center, Durham, NC 27710. Tel.: 919-613-8627; Fax: 919-681-1005; E-mail: daniel.lew{at}

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