TGFβ-TAZ/SRF signalling regulates vascular smooth muscle cell differentiation.
Vascular smooth muscle cells (VSMCs) do not terminally differentiate; they modulate their phenotype between proliferative and differentiated states, which is a major factor contributing to vascular diseases. TGFβ signalling has been implicated in inducing VSMC differentiation, although the exact mechanism remains largely unknown. Our goal was to assess the network of transcription factors involved in the induction of VSMC differentiation, and to determine the role of TAZ in promoting the quiescent VSMC phenotype. TGFβ robustly induces VSMC marker genes in 10T1/2 mouse embryonic fibroblast cells and the potent transcriptional regulator TAZ has been shown to retain Smad complexes on DNA. Thus, the role of TAZ in regulation of VSMC differentiation was studied. Using primary aortic VSMCs coupled with siRNA-mediated gene silencing, our studies reveal that TAZ is required for TGFβ induction of smooth muscle genes and is also required for the differentiated VSMC phenotype; synergy between TAZ and SRF, and TAZ and Myocardin (MyoC856), in regulating smooth muscle gene activation was observed. These data provide evidence of components of a novel signalling pathway that links TGFβ signalling to induction of smooth muscle genes through a mechanism involving regulation of TAZ and SRF proteins. In addition, we report a physical interaction of TAZ and MyoC856. These observations elucidate a novel level of control of VSMC induction which may have implications for vascular diseases and congenital vascular malformations.
Department of Biology, York University, Toronto, ON, Canada.|Muscle Health Research Centre (MHRC), York University, Toronto, ON, Canada.|Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, ON, Canada.
Christina
C
Pagiatakis
Department of Biology, York University, Toronto, ON, Canada.|Muscle Health Research Centre (MHRC), York University, Toronto, ON, Canada.|Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, ON, Canada.
Dandan
D
Sun
Department of Biology, York University, Toronto, ON, Canada.|Muscle Health Research Centre (MHRC), York University, Toronto, ON, Canada.|Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, ON, Canada.
Stephanie W
SW
Tobin
Department of Biology, York University, Toronto, ON, Canada.
Tetsuaki
T
Miyake
Department of Biology, York University, Toronto, ON, Canada.|Muscle Health Research Centre (MHRC), York University, Toronto, ON, Canada.|Centre for Research in Biomolecular Interactions (CRBI), York University, Toronto, ON, Canada.|Centre for Research in Mass Spectrometry (CRMS), York University, Toronto, ON, Canada.
John C
JC
McDermott
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001011:Aorta; D002460:Cell Line; D002478:Cells, Cultured; D005347:Fibroblasts; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D008809:Mice, Inbred C3H; D024510:Muscle Development / Q000235:genetics / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology*; D025941:Protein Interaction Mapping; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D026362:Serum Response Factor / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000099251:Myocardin
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D026362:Serum Response Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099251:Myocardin; C517794:Wwtr1 protein, mouse

SRF
; 
TAZ
; 
VSMC
; TGFβ; myocardin