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Curr Biol

Title:		Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway
Author(s):		Brown JL; Stowers L; Baer M; Trejo J; Coughlin S; Chant J;
Address:		"Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA"
Journal Title:		Curr Biol
Year:		1996
Volume:		6
Issue:		5
Page Number:		598 - 605
DOI:		10.1016/s0960-9822(02)00546-8
ISSN/ISBN:		0960-9822 (Print) 0960-9822 (Linking)
Abstract:		"BACKGROUND: The Rho-related GTP-binding proteins Cdc42 and Rac1 have been shown to regulate signaling pathways involved in cytoskeletal reorganization and stress-responsive JNK (Jun N-terminal kinase) activation. However, to date, the GTPase targets that mediate these effects have not been identified. PAK defines a growing family of mammalian kinases that are related to yeast Ste20 and are activated in vitro through binding to Cdc42 and Rac1 (PAK: p21 Cdc42-/Rac-activated kinase). Clues to PAK function have come from studies of Ste20, which controls the activity of the yeast mating mitogen-activated protein (MAP) kinase cascade, in response to a heterotrimeric G protein and Cdc42. RESULTS: To initiate studies of mammalian Ste20-related kinases, we identified a novel human PAK isoform, hPAK1. When expressed in yeast, hPAK1 was able to replace Ste20 in the pheromone response pathway. Chemical mutagenesis of a plasmid encoding hPAK1, followed by transformation into yeast, led to the identification of a potent constitutively active hPAK1 with a substitution of a highly conserved amino-acid residue (L107F) in the Cdc42-binding domain. Expression of the hPAK1(L107F) allele in mammalian cells led to specific activation of the Jun N-terminal kinase MAP kinase pathway, but not the mechanistically related extracellular signal-regulated MAP kinase pathway. CONCLUSIONS: These results demonstrate that hPAK1 is a GTPase effector controlling a downstream MAP kinase pathway in mammalian cells, as Ste20 does in yeast. Thus, PAK and Ste20 kinases play key parts in linking extracellular signals from membrane components, such as receptor-associated G proteins and Rho-related GTPases, to nuclear responses, such as transcriptional activation"
Keywords:		"Alleles Amino Acid Sequence Base Sequence Calcium-Calmodulin-Dependent Protein Kinases/*metabolism Cell Cycle Proteins/metabolism Cloning, Molecular DNA, Complementary Enzyme Activation GTP Phosphohydrolases/*metabolism GTP-Binding Proteins/metabolism Hum;"
Notes:		"MedlineBrown, J L Stowers, L Baer, M Trejo, J Coughlin, S Chant, J eng Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. England 1996/05/01 Curr Biol. 1996 May 1; 6(5):598-605. doi: 10.1016/s0960-9822(02)00546-8"