PMID- 23145787
OWN - NLM
STAT- MEDLINE
DCOM- 20130307
LR  - 20130110
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 449
IP  - 3
DP  - 2013 Feb 1
TI  - Ras-guanine-nucleotide-releasing factors 1 and 2 interact with PLCgamma at focal 
      adhesions to enable IL-1-induced Ca(2+) signalling, ERK activation and MMP-3 
      expression.
PG  - 771-82
LID - 10.1042/BJ20121170 [doi]
AB  - IL (interleukin)-1 signalling in anchorage-dependent cells involves 
      focal-adhesion-restricted and Ca2+-dependent Ras and ERK 
      (extracellular-signal-regulated kinase) activation that leads to MMP (matrix 
      metalloproteinase) release and extracellular matrix remodelling. Ras activity is 
      regulated, in part, by the Ca2+-responsive Ras GRFs (guanine-nucleotide-releasing 
      factors) 1 and 2, but the mechanisms that link and localize IL-1-induced Ca2+ 
      signalling to focal adhesions are not defined. In the present study we 
      characterized the role of Ras-GRF1/2 in Ca2+ and Ras-->ERK signalling after IL-1 
      stimulation. By immunoprecipitation we found that Ras-GRF1/2 associates with 
      PLCgamma1 (phospholipase Cgamma1). This association enables PLCgamma1 recruitment to focal 
      adhesions and is required for Ras signalling, ERK activation and MMP-3 release 
      downstream of IL-1 stimulation. Depletion of PLCgamma1 by siRNA (small interfering 
      RNA) 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. The results of the present study show that, in addition to their 
      functions as Ras-exchange factors, Ras-GRF1 and -GRF2 may act as adaptors that 
      bind PLCgamma1 and restrict Ca2+ signalling 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.
FAU - Wang, Qin
AU  - Wang Q
AD  - Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, 
      Canada, M5S 3E2.
FAU - Siminovitch, Katherine A
AU  - Siminovitch KA
FAU - Downey, Gregory P
AU  - Downey GP
FAU - McCulloch, Christopher A
AU  - McCulloch CA
LA  - eng
GR  - HL090669/HL/NHLBI NIH HHS/United States
GR  - MOP-384254/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Interleukin-1)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Rasgrf1 protein, mouse)
RN  - 0 (Rasgrf2 protein, mouse)
RN  - 0 (ras Guanine Nucleotide Exchange Factors)
RN  - 0 (ras-GRF1)
RN  - EC 3.1.4.3 (Phospholipase C gamma)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.17 (Mmp3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Calcium Signaling/drug effects
MH  - Focal Adhesions/*metabolism
MH  - Interleukin-1/pharmacology
MH  - MAP Kinase Signaling System/drug effects
MH  - Matrix Metalloproteinase 3/*metabolism
MH  - Mice
MH  - NIH 3T3 Cells
MH  - Phospholipase C gamma/antagonists & inhibitors/genetics/*metabolism
MH  - Phosphorylation
MH  - RNA, Small Interfering/genetics
MH  - ras Guanine Nucleotide Exchange Factors/*metabolism
MH  - ras-GRF1/*metabolism
EDAT- 2012/11/14 06:00
MHDA- 2013/03/08 06:00
CRDT- 2012/11/14 06:00
PHST- 2012/11/14 06:00 [entrez]
PHST- 2012/11/14 06:00 [pubmed]
PHST- 2013/03/08 06:00 [medline]
AID - BJ20121170 [pii]
AID - 10.1042/BJ20121170 [doi]
PST - ppublish
SO  - Biochem J. 2013 Feb 1;449(3):771-82. doi: 10.1042/BJ20121170.