title: ArhGAP15, a Rac-specific GTPase-activating protein, plays a dual role in inhibiting small GTPase signaling.
abstract: Signaling from small GTPases is a tightly regulated process. In this work we used a protein microarray screen to identify the Rac-specific GAP, ArhGAP15, as a substrate of the Rac effectors Pak1 and Pak2. In addition to serving as a substrate of Pak1/2, we found that ArhGAP15, via its PH domain, bound to these kinases. The association of ArhGAP15 to Pak1/2 resulted in mutual inhibition of GAP and kinase catalytic activity, respectively. Knock-down of ArhGAP15 resulted in activation of Pak1/2, both indirectly, as a result of Rac activation, and directly, as a result of disruption of the ArhGAP15/Pak complex. Our data suggest that ArhGAP15 plays a dual negative role in regulating small GTPase signaling, by acting at the level of the GTPase itself, as well interacting with its effector, Pak kinase.
authors.affiliation: From the Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: Maria
authors.initials: M
authors.lastname: Radu
authors.affiliation: the Department of Biochemistry and Molecular Biology, Drexel University, Philadelphia, Pennsylvania 19102, and.
authors.forename: Sonali J
authors.initials: SJ
authors.lastname: Rawat
authors.affiliation: From the Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
authors.forename: Alexander
authors.initials: A
authors.lastname: Beeser
authors.affiliation: the Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Anton
authors.initials: A
authors.lastname: Iliuk
authors.affiliation: the Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907.
authors.forename: Weiguo Andy
authors.initials: WA
authors.lastname: Tao
authors.affiliation: From the Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,. Electronic address: Jonathan.Chernoff@fccc.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000595:Amino Acid Sequence; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013379:Substrate Specificity; D054462:p21-Activated Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C473316:ARHGAP15 protein, human; D020690:GTPase-Activating Proteins; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020744:rac GTP-Binding Proteins
keywords: ERK; Protein Kinases; Protein Phosphorylation; Signal Transduction; Small GTPases