PMID- 28655771
OWN - NLM
STAT- MEDLINE
DCOM- 20170912
LR  - 20210314
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 292
IP  - 34
DP  - 2017 Aug 25
TI  - p115 RhoGEF activates the Rac1 GTPase signaling cascade in MCP1 chemokine-induced 
      vascular smooth muscle cell migration and proliferation.
PG  - 14080-14091
LID - S0021-9258(20)34225-3 [pii]
LID - 10.1074/jbc.M117.777896 [doi]
AB  - Although the involvement of Rho proteins in the pathogenesis of vascular diseases 
      is well studied, little is known about the role of their upstream regulators, the 
      Rho guanine nucleotide exchange factors (RhoGEFs). Here, we sought to identify 
      the RhoGEFs involved in monocyte chemotactic protein 1 (MCP1)-induced vascular 
      wall remodeling. We found that, among the RhoGEFs tested, MCP1 induced tyrosine 
      phosphorylation of p115 RhoGEF but not of PDZ RhoGEF or leukemia-associated 
      RhoGEF in human aortic smooth muscle cells (HASMCs). Moreover, p115 RhoGEF 
      inhibition suppressed MCP1-induced HASMC migration and proliferation. Consistent 
      with these observations, balloon injury (BI) induced p115 RhoGEF tyrosine 
      phosphorylation in rat common carotid arteries, and siRNA-mediated 
      down-regulation of its levels substantially attenuated BI-induced smooth muscle 
      cell migration and proliferation, resulting in reduced neointima formation. 
      Furthermore, depletion of p115 RhoGEF levels also abrogated MCP1- or BI-induced 
      Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling, which, as we reported 
      previously, is involved in vascular wall remodeling. Our findings also show that 
      protein kinase N1 (PKN1) downstream of Rac1-cyclin D1/CDK6 and upstream of 
      CDK4-PAK1 in the p115 RhoGEF-Rac1-NFATc1-cyclin D1-CDK6-PKN1-CDK4-PAK1 signaling 
      axis is involved in the modulation of vascular wall remodeling. Of note, we also 
      observed that CCR2-G(i/o)-Fyn signaling mediates MCP1-induced p115 RhoGEF and 
      Rac1 GTPase activation. These findings suggest that p115 RhoGEF is critical for 
      MCP1-induced HASMC migration and proliferation in vitro and for injury-induced 
      neointima formation in vivo by modulating Rac1-NFATc1-cyclin 
      D1-CDK6-PKN1-CDK4-PAK1 signaling.
CI  - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Singh, Nikhlesh K
AU  - Singh NK
AD  - From the Department of Physiology, University of Tennessee Health Science Center, 
      Memphis, Tennessee 38163. Electronic address: nsingh2@uthsc.edu.
FAU - Janjanam, Jagadeesh
AU  - Janjanam J
AD  - From the Department of Physiology, University of Tennessee Health Science Center, 
      Memphis, Tennessee 38163.
FAU - Rao, Gadiparthi N
AU  - Rao GN
AD  - From the Department of Physiology, University of Tennessee Health Science Center, 
      Memphis, Tennessee 38163. Electronic address: rgadipar@uthsc.edu.
LA  - eng
GR  - R01 HL064165/HL/NHLBI NIH HHS/United States
GR  - R01 HL069908/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20170627
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (ARHGEF1 protein, human)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (RAC1 protein, human)
RN  - 0 (Rho Guanine Nucleotide Exchange Factors)
RN  - EC 3.6.5.2 (rac1 GTP-Binding Protein)
SB  - IM
MH  - Animals
MH  - Aorta
MH  - Carotid Artery Injuries/metabolism/pathology
MH  - Carotid Artery, Common
MH  - Cell Movement
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Chemokine CCL2/*agonists/metabolism
MH  - Enzyme Activation
MH  - Humans
MH  - *Models, Biological
MH  - Muscle, Smooth, Vascular/cytology/injuries/*metabolism/pathology
MH  - Neointima/metabolism/pathology
MH  - Phosphorylation
MH  - *Protein Processing, Post-Translational
MH  - RNA Interference
MH  - Rats
MH  - Rho Guanine Nucleotide Exchange Factors/antagonists & 
      inhibitors/genetics/metabolism
MH  - *Signal Transduction
MH  - Substrate Specificity
MH  - Vascular Remodeling
MH  - rac1 GTP-Binding Protein/*agonists/metabolism
PMC - PMC5572933
OTO - NOTNLM
OT  - NFAT transcription factor
OT  - cell migration
OT  - cell proliferation
OT  - guanine nucleotide exchange factor (GEF)
OT  - vascular smooth muscle cells
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2017/06/29 06:00
MHDA- 2017/09/13 06:00
PMCR- 2018/08/25
CRDT- 2017/06/29 06:00
PHST- 2017/01/23 00:00 [received]
PHST- 2017/06/20 00:00 [revised]
PHST- 2017/06/29 06:00 [pubmed]
PHST- 2017/09/13 06:00 [medline]
PHST- 2017/06/29 06:00 [entrez]
PHST- 2018/08/25 00:00 [pmc-release]
AID - S0021-9258(20)34225-3 [pii]
AID - M117.777896 [pii]
AID - 10.1074/jbc.M117.777896 [doi]
PST - ppublish
SO  - J Biol Chem. 2017 Aug 25;292(34):14080-14091. doi: 10.1074/jbc.M117.777896. Epub 
      2017 Jun 27.