Article
- The EMBO Journal (2006) 25, 2062 - 2074
- doi:10.1038/sj.emboj.7601098
Published online: 20 April 2006
Subject Category:
Phospholipase C
/diacylglycerol-dependent activation of 
2-chimaerin restricts EGF-induced Rac signaling
HongBin Wang1, Chengfeng Yang1, Federico Coluccio Leskow1, Jing Sun1, Bertram Canagarajah2, James H Hurley2 and Marcelo G Kazanietz1
- Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, MD, USA
Correspondence to:
Marcelo G Kazanietz, Department of Pharmacology, University of Pennsylvania School of Medicine, 816 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160, USA. Tel.: +1 215 898 0253; Fax: +1 215 573 9004; E-mail: marcelo@spirit.gcrc.upenn.edu
Received 17 October 2005; Accepted 27 March 2006
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 
2-chimaerin as an effector of the epidermal growth factor receptor (EGFR) via coupling to phospholipase C
(PLC) and generation of the lipid second messenger diacylglycerol (DAG). EGF redistributes 2-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 2-chimaerin C1 domain as well as by PLC1 RNAi, thus defining 2-chimaerin as a novel DAG effector. On the other hand, GAP-deficient 2-chimaerin mutants show enhanced translocation and sustained Rac1 association in the FRET assays. Remarkably, RNAi depletion of 2-chimaerin significantly extended the duration of Rac activation by EGF, suggesting that 2-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.
Keywords:
- 2-chimaerin,
- diacylglycerol,
- EGF,
- Phorbol esters,
- Rac
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