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Molecular and Cellular Biology, January 1999, p. 602-611, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Genetic Evidence for Pak1 Autoinhibition and Its Release by Cdc42

Hua Tu1,2,dagger and Mike Wigler1,*

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724,1 and Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, Stony Brook, New York 117942

Received 4 June 1998/Returned for modification 6 July 1998/Accepted 15 September 1998

Pak1 protein kinase of Schizosaccharomyces pombe, a member of the p21-GTPase-activated protein kinase (PAK) family, participates in signaling pathways including sexual differentiation and morphogenesis. The regulatory domain of PAK proteins is thought to inhibit the kinase catalytic domain, as truncation of this region renders kinases more active. Here we report the detection in the two-hybrid system of the interaction between Pak1 regulatory domain and the kinase catalytic domain. Pak1 catalytic domain binds to the same highly conserved region on the regulatory domain that binds Cdc42, a GTPase protein capable of activating Pak1. Two-hybrid, mutant, and genetic analyses indicated that this intramolecular interaction rendered the kinase in a closed and inactive configuration. We show that Cdc42 can induce an open configuration of Pak1. We propose that Cdc42 interaction disrupts the intramolecular interactions of Pak1, thereby releasing the kinase from autoinhibition.

* Corresponding author. Mailing address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. Phone: (516) 367-8376. Fax: (516) 367-8381. E-mail: wigler{at}cshl.org.

dagger Present address: Tularik, Inc., South San Francisco, CA 94080.

Molecular and Cellular Biology, January 1999, p. 602-611, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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