ArhGAP15, a Rac-specific GTPase-activating Protein, Plays a Dual Role in Inhibiting Small GTPase Signaling

J Biol Chem. 2013 Jul 19;288(29):21117-25. doi: 10.1074/jbc.M113.459719. Epub 2013 Jun 11.

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.

Keywords: ERK; Protein Kinases; Protein Phosphorylation; Signal Transduction; Small GTPases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Down-Regulation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTPase-Activating Proteins / antagonists & inhibitors
  • GTPase-Activating Proteins / chemistry
  • GTPase-Activating Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System
  • Models, Biological
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Signal Transduction*
  • Substrate Specificity
  • p21-Activated Kinases / metabolism
  • rac GTP-Binding Proteins / antagonists & inhibitors*
  • rac GTP-Binding Proteins / metabolism*

Substances

  • ARHGAP15 protein, human
  • GTPase-Activating Proteins
  • p21-Activated Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • rac GTP-Binding Proteins