PathwayStep109 Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4 PathwayStep5442 PathwayStep5443 PathwayStep5444 PathwayStep5445 PathwayStep5449 PathwayStep5448 PathwayStep5447 PathwayStep5446 PathwayStep5478 Phosphorylated SMAD2/3 dissociates from TGFBR Activated type I receptor phosphorylates SMAD2/3 directly An anchoring protein, SARA, recruits SMAD2/3 TGFBR2 phosphorylates TGFBR1 Dimeric TGFB1 binds to TGFBR2 homodimer TGFBR2 recruits TGFBR1 Latent TGF-beta-1 is cleaved by furin Secretion and activation of the latent large complex of TGF-beta-1 TGF-beta receptor signaling activates SMADs Authored: Orlic-Milacic, M, 2012-04-04 Binding of transforming growth factor beta 1 (TGF beta 1, i.e. TGFB1) to TGF beta receptor type 2 (TGFBR2) activates TGF beta receptor signaling cascade. TGFB1 is posttranslationally processed by furin (Dubois et al. 1995) to form a homodimer and secreted to the extracellular space as part of the large latent complex (LLC). After the LLC disassembles in the extracellular space, dimeric TGFB1 becomes capable of binding to TGFBR2 (Annes et al. 2003, Keski Oja et al. 2004). Formation of TGFB1:TGFBR2 complex creates a binding pocket for TGF-beta receptor type-1 (TGFBR1) and TGFBR1 is recruited to the complex by binding to both TGFB1 and TGFBR2. This results in an active heterotetrameric TGF-beta receptor complex that consists of TGFB1 homodimer bound to two heterodimers of TGFBR1 and TGFBR2 (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). TGF-beta signaling can also occur through a single heterodimer of TGFBR1 and TGFBR2, although with decreased efficiency (Huang et al. 2011). TGFBR1 and TGFBR2 interact through their extracellular domains, which brings their cytoplasmic domains together. Ligand binding to extracellular receptor domains is cooperative, but no conformational change is seen from crystal structures of either TGFB1- or TGFB3-bound heterotetrameric receptor complexes (Groppe et al. 2008, Radaev et al. 2010).<br><br>Activation of TGFBR1 by TGFBR2 in the absence of ligand is prevented by FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase. FKBP1A forms a complex with inactive TGFBR1 and dissociates from it only after TGFBR1 is recruited by TGFB1-bound TGFBR2 (Chen et al. 1997). <br><br>Both TGFBR1 and TGFBR2 are receptor serine/threonine kinases. Formation of the hetero-tetrameric TGF-beta receptor complex (TGFBR) in response to TGFB1 binding induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. TGFBR2 trans-phosphorylates serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of TGFBR1 (Wrana et al. 1994, Souchelnytskyi et al. 1996), activating TGFBR1.<br>In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta stimulation. Sumoylation enhances TGFBR1 kinase activity (Kang et al. 2008). <br><br>The activated TGFBR complex is internalized by clathrin-mediated endocytosis into early endosomes. With the assistance of SARA, an early endosome membrane protein, phosphorylated TGFBR1 within TGFBR complex recruits SMAD2 and/or SMAD3 , i.e. R-SMADs (Tsukazaki et al. 1998). TGFBR1 phosphorylates recruited SMAD2/3 on two C-terminal serine residues (Souchelnytskyi et al. 2001). The phosphorylation changes the conformation of SMAD2/3 MH2 domain, promoting dissociation of SMAD2/3 from SARA and TGFBR1 (Souchelnytskyi et al. 1997, Macias-Silva et al. 1996, Nakao et al. 1997) and formation of SMAD2/3 trimers (Chacko et al. 2004). The phosphorylated C-terminal tail of SMAD2/3 has high affinity for SMAD4 (Co-SMAD), inducing formation of SMAD2/3:SMAD4 heterotrimers, composed of two phosphorylated R-SMADs (SMAD2 and/or SMAD3) and SMAD4 (Co-SMAD). SMAD2/3:SMAD4 heterotrimers are energetically favored over R-SMAD trimers (Nakao et al. 1997, Qin et al. 2001, Kawabata et al. 1998, Chacko et al. 2004). <br>SMAD2/3:SMAD4 heterotrimers translocate to the nucleus where they act as transcriptional regulators. Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0007179 Pubmed11100470 Pubmed11779505 Pubmed12482908 Pubmed1333888 Pubmed15350224 Pubmed15564041 Pubmed18243111 Pubmed20207738 Pubmed21423151 Pubmed7693660 Pubmed7737999 Pubmed8047140 Pubmed8242743 Pubmed8947046 Pubmed8980228 Pubmed9233797 Pubmed9311995 Pubmed9346966 Pubmed9670020 Pubmed9865696 Reactome Database ID Release 432173789 Reactome, http://www.reactome.org ReactomeREACT_120850 Reviewed: Huang, Tao, 2012-05-14 Downregulation of TGF-beta receptor signaling