PathwayStep5485 PathwayStep5484 PathwayStep5483 PathwayStep5482 PathwayStep5481 PathwayStep5480 SMURF1 ubiquitinates RHOA Disassembly of tight junctions TGFBR2 is recruited to tight junctions after TGF-beta stimulation TGFBR1 is recruited to tight junctions by PARD6A SMURF1 binds phosphorylated PARD6A TGFBR2 phosphorylates TGFBR1 and PARD6A TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0007179 In normal cells and in the early stages of cancer development, signaling by TGF-beta plays a tumor suppressive role, as SMAD2/3:SMAD4-mediated transcription inhibits cell division by downregulating MYC oncogene transcription and stimulating transcription of CDKN2B tumor suppressor gene. In advanced cancers however, TGF-beta signaling promotes metastasis by stimulating epithelial to mesenchymal transition (EMT). <br>TGFBR1 is recruited to tight junctions by binding PARD6A, a component of tight junctions. After TGF-beta stimulation, activated TGFBR2 binds TGFBR1 at tight junctions, and phosphorylates both TGFBR1 and PARD6A. Phosphorylated PARD6A recruits SMURF1 to tight junctions. SMURF1 is able to ubiquitinate RHOA, a component of tight junctions needed for tight junction maintenance, leading to disassembly of tight junctions, an important step in EMT (Wang et al. 2003, Ozdamar et al. 2005). Pubmed14657501 Pubmed15761148 Reactome Database ID Release 432173791 Reactome, http://www.reactome.org ReactomeREACT_120726 Reviewed: Huang, Tao, 2012-05-14