FGFR1 forms an FRS2-dependent complex with mTOR to regulate smooth muscle marker gene expression.
Vascular smooth muscle cells (VSMCs) switch from a contractile to a synthetic phenotype in human cardiovascular disease such as atherosclerosis and restenosis after angioplasty. VSMCs show reduced expression of contractile proteins and are capable of responding to mitogens by increasing expression of growth factor receptors. Fibroblast growth factor receptor-1 (FGFR1) signaling is one of several signaling pathways involved in this VSMC phenotypic switching. The aim of this study was to examine the signaling pathway downstream of FGFR1 in the regulation of SM marker gene expression. We found that FGFR1 activated Akt/mTOR pathway and that the mTOR inhibitor rapamycin partially reversed FGFR1-mediated downregulation of SM marker gene expression. Furthermore, we showed that mTOR forms a multi-protein complex with FGFR1 in VSMCs. These findings provide novel information for future development of therapeutic strategies for the treatment of human cardiovascular disease.
Chen
Pei-Yu
PY
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074-7205, USA. chenp@mmc.org
Friesel
Robert
R
D000199:Actins / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D005786:Gene Expression Regulation; D005819:Genetic Markers; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D005819:Genetic Markers; D008565:Membrane Proteins; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D051496:Receptor, Fibroblast Growth Factor, Type 1; D058570:TOR Serine-Threonine Kinases; C106534:FRS2 protein, human; C498862:Acta2 protein, rat; C546842:MTOR protein, human; C546845:mTOR protein, rat