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Molecular and Cellular Biology, February 2006, p. 912-928, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.912-928.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The RA Domain of Ste50 Adaptor Protein Is Required for Delivery of Ste11 to the Plasma Membrane in the Filamentous Growth Signaling Pathway of the Yeast Saccharomyces cerevisiae{dagger}

Dagmar M. Truckses,{ddagger} Joshua E. Bloomekatz,§ and Jeremy Thorner*

Department of Molecular and Cell Biology, Division of Biochemistry and Molecular Biology, University of California, Room 401, Barker Hall, Berkeley, California 94720-3202

Received 25 December 2004/ Returned for modification 3 February 2005/ Accepted 3 November 2005

In Saccharomyces cerevisiae, pheromone response requires Ste5 scaffold protein, which ensures efficient G-protein-dependent recruitment of mitogen-activated protein kinase (MAPK) cascade components Ste11 (MAPK kinase kinase), Ste7 (MAPK kinase), and Fus3 (MAPK) to the plasma membrane for activation by Ste20 protein kinase. Ste20, which phosphorylates Ste11 to initiate signaling, is activated by binding to Cdc42 GTPase (membrane anchored via its C-terminal geranylgeranylation). Less clear is how activated and membrane-localized Ste20 contacts Ste11 to trigger invasive growth signaling, which also requires Ste7 and the MAPK Kss1, but not Ste5. Ste50 protein associates constitutively via an N-terminal sterile-alpha motif domain with Ste11, and this interaction is required for optimal invasive growth and hyperosmotic stress (high-osmolarity glycerol [HOG]) signaling but has a lesser role in pheromone response. We show that a conserved C-terminal, so-called "Ras association" (RA) domain in Ste50 is also essential for invasive growth and HOG signaling in vivo. In vitro the Ste50 RA domain is not able to associate with Ras2, but it does associate with Cdc42 and binds to a different face than does Ste20. RA domain function can be replaced by the nine C-terminal, plasma membrane-targeting residues (KKSKKCAIL) of Cdc42, and membrane-targeted Ste50 also suppresses the signaling deficiency of cdc42 alleles specifically defective in invasive growth. Thus, Ste50 serves as an adaptor to tether Ste11 to the plasma membrane and can do so via association with Cdc42, thereby permitting the encounter of Ste11 with activated Ste20.

* Corresponding author. Mailing address: Department of Molecular and Cell Biology, Division of Biochemistry and Molecular Biology, University of California, Room 16, Barker Hall, Berkeley, CA 94720-3202. Phone: (510) 642-2558. Fax: (510) 642-6420. E-mail: jthorner{at}berkeley.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Biochemistry and Molecular Biology, University of Texas-M. D. Anderson Cancer Center, Box 117, 1515 Holcombe Blvd., Houston, TX 77030.

§ Present address: Program in Cell Biology and Genetics, Weill Graduate School of Medical Sciences, Cornell University, 445 East 69th Street, New York, NY 10021.

Molecular and Cellular Biology, February 2006, p. 912-928, Vol. 26, No. 3
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.3.912-928.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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