Regulation of the p21-activated kinase (PAK) by a human Gβ-like WD-repeat protein, hPIP1

Chunzhi Xia, Wenbin Ma, Lewis Joe Stafford, Stevan Marcus, Wen Cheng Xiong, Mingyao Liu

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

The family of p21-activated protein kinases (PAKs) is composed of serine-threonine kinases whose activity is regulated by the small guanosine triphosphatases (GTPases) Rac and Cdc42. In mammalian cells, PAKs have been implicated in the regulation of mitogen-activated protein cascades, cellular morphological and cytoskeletal changes, neurite outgrowth, and cell apoptosis. Although the ability of Cdc42 and Rac GTPases to activate PAK is well established, relatively little is known about the negative regulation of PAK or the identity of PAK cellular targets. Here, we describe the identification and characterization of a human PAK-interacting protein, hPIP1. hPIP1 contains G protein β-like WD repeats and shares sequence homology with the essential fission yeast PAK regulator, Skb15, as well as the essential budding yeast protein, MAK11. Interaction of hPIP1 with PAK1 inhibits the Cdc42/Rac-stimulated kinase activity through the N-terminal regulatory domains of PAK1. Cotransfection of hPIP1 in mammalian cells inhibits PAK-mediated c-Jun N-terminal kinase and nuclear factor κ B signaling pathways. Our results demonstrate that hPIP1 is a negative regulator of PAK and PAK signaling pathways.

Original languageEnglish (US)
Pages (from-to)6174-6179
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number11
DOIs
StatePublished - May 22 2001

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