Phospholipase Cγ/diacylglycerol-dependent activation of β2-chimaerin restricts EGF-induced Rac signaling

Hong Bin Wang, Chengfeng Yang, Federico Coluccio Leskow, Jing Sun, Bertram Canagarajah, James H. Hurley, Marcelo G. Kazanietz

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Although receptor-mediated regulation of small G-proteins and the cytoskeleton is intensively studied, the mechanisms for attenuation of these signals are poorly understood. In this study, we have identified the Rac-GAP β2-chimaerin as an effector of the epidermal growth factor receptor (EGFR) via coupling to phospholipase Cγ (PLCγ) and generation of the lipid second messenger diacylglycerol (DAG). EGF redistributes β2-chimaerin to promote its association with the small GTPase Rac1 at the plasma membrane, as determined by FRET. This relocalization and association with Rac1 were impaired by disruption of the β2-chimaerin C1 domain as well as by PLCγ1 RNAi, thus defining β2-chimaerin as a novel DAG effector. On the other hand, GAP-deficient β2-chimaerin mutants show enhanced translocation and sustained Rac1 association in the FRET assays. Remarkably, RNAi depletion of β2-chimaerin significantly extended the duration of Rac activation by EGF, suggesting that β2-chimaerin serves as a mechanism that self-limits Rac activity in response to EGFR activation. Our results represent the first direct evidence of divergence in DAG signaling downstream of a tyrosine-kinase receptor via a PKC-independent mechanism.

Original languageEnglish
Pages (from-to)2062-2074
Number of pages13
JournalEMBO Journal
Volume25
Issue number10
DOIs
StatePublished - May 17 2006

Keywords

  • Diacylglycerol
  • EGF
  • Phorbol esters
  • Rac
  • β2-chimaerin

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology

Fingerprint

Dive into the research topics of 'Phospholipase Cγ/diacylglycerol-dependent activation of β2-chimaerin restricts EGF-induced Rac signaling'. Together they form a unique fingerprint.

Cite this