Document Detail


Ras-guanine nucleotide releasing factors 1 and 2 interact with PLCγ at focal adhesions to enable IL-1-induced Ca2+ signaling, ERK activation and MMP-3 expression.
MedLine Citation:
PMID:  23145787     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Interleukin-1 (IL-1) signaling in anchorage-dependent cells involves focal adhesion-restricted and Ca2+-dependent Ras and extracellular signal-related kinase (ERK) activation that lead to MMP release and extracellular matrix remodeling. Ras activity is regulated in part by the Ca2+-responsive Ras guanine-nucleotide-releasing factors 1 and 2 (Ras-GRF1/2), but the mechanisms that link and localize IL-1-induced Ca2+ signaling to focal adhesions are not defined. Herein we characterized the role of Ras-GRF1/2 in Ca2+ and Ras→ERK signaling after IL-1 stimulation. By immunoprecipitation we found that Ras-GRF1/2 associates with PLCγ1. This association enables PLCγ1 recruitment to focal adhesions and is required for Ras signaling, ERK activation and MMP-3 release downstream of IL-1 stimulation. Depletion of PLCγ1 by siRNA abolished IL-1-induced Ras activation and MMP-3 expression. Buffering of cytosolic Ca2+ reduced Ras interactions with Ras-GRF1/2 and blocked MMP-3 release. Our results show that in addition to their functions as Ras exchange factors, Ras-GRF1 and GRF2 may act as adaptors that bind PLCγ1 and restrict Ca2+-signaling to the vicinity of focal adhesions, indicating a new role for these GRFs that is required for IL-1 induction of the Ras→ERK pathway and MMP-3 expression.
Authors:
Qin Wang; Katherine A Siminovitch; Gregory P Downey; Christopher A McCulloch
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-13
Journal Detail:
Title:  The Biochemical journal     Volume:  -     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-13     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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