FEATURES

FAMILY

DESCRIPTION

Also known as SMAD3_HUMAN, SMAD3, MADH3. Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. Also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. Has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive. Regulator of chondrogenesis and osteogenesis and inhibits early healing of bone fractures. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. Monomer; in the absence of TGF-beta (PubMed:9670020). Homooligomer; in the presence of TGF-beta (PubMed:9670020). Heterotrimer; forms a heterotrimer in the presence of TGF-beta consisting of two molecules of C-terminally phosphorylated SMAD2 or SMAD3 and one of SMAD4 to form the transcriptionally active SMAD2/SMAD3-SMAD4 complex (PubMed:9670020, PubMed:11224571, PubMed:15799969, PubMed:15350224). Part of a complex consisting of AIP1, ACVR2A, ACVR1B and SMAD3 (PubMed:9892009). Forms a complex with SMAD2 and TRIM33 upon addition of TGF-beta (PubMed:16751102). Found in a complex composed of SMAD3, RAN and XPO4; within the complex interacts directly with XPO4 (PubMed:16449645). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta (PubMed:9732876, PubMed:10995748). Interacts (via an N-terminal domain) with JUN (via its basic DNA binding and leucine zipper domains); this interaction is essential for DNA binding and cooperative transcriptional activity in response to TGF-beta (PubMed:9732876, PubMed:10995748). Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and SMAD4 (PubMed:24324267). Interacts with PPM1A; the interaction dephosphorylates SMAD3 in the C-terminal SXS motif leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of TGF-beta signaling (PubMed:16751101). Interacts (via MH2 domain) with ZMIZ1 (via SP-RING-type domain); in the TGF-beta signaling pathway increases the activity of the SMAD3/SMAD4 transcriptional complex (PubMed:16777850). Interacts (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the transcriptional responses by mediating ubiquitination and degradation of SMAD3 inhibitors (PubMed:9311995). Interacts (dephosphorylated form via the MH1 and MH2 domains) with RANBP3 (via its C-terminal R domain); the interaction results in the export of dephosphorylated SMAD3 out of the nucleus and termination of the TGF-beta signaling (PubMed:19289081). Interacts (via MH2 domain) with LEMD3; the interaction represses SMAD3 transcriptional activity through preventing the formation of the heteromeric complex with SMAD4 and translocation to the nucleus (PubMed:15601644, PubMed:15647271). Interacts (via the linker region) with EP300 (C-terminal); the interaction promotes SMAD3 acetylation and is enhanced by TGF-beta phosphorylation in the C-terminal of SMAD3 (PubMed:9843571, PubMed:15588252). This interaction can be blocked by competitive binding of adenovirus oncoprotein E1A to the same C-terminal site on EP300, which then results in partially inhibited SMAD3/SMAD4 transcriptional activity (PubMed:9843571, PubMed:15588252). Interacts with TGFBR1 (PubMed:9311995). Interacts with TGFB1I1 (PubMed:15561701). Interacts with PRDM16 (PubMed:19049980). Interacts with SNW1 (PubMed:11278756). Interacts (via MH2 domain) with ZFYVE9 (PubMed:9865696, PubMed:12154125). Interacts with HDAC1 (PubMed:19049980). Interacts with TGIF2 (PubMed:11427533). Interacts with SKOR1 (PubMed:17292623). Interacts with SKOR2 (PubMed:16200078). Interacts with DACH1; the interaction inhibits the TGF-beta signaling (PubMed:14525983). Interacts with RBPMS (PubMed:17099224). Interacts (via MH2 domain) with MECOM (PubMed:9665135, PubMed:15897867). Interacts with WWTR1 (via its coiled-coil domain) (PubMed:18568018). Interacts with SKI; the interaction represses SMAD3 transcriptional activity (PubMed:19049980). Interacts with MEN1 (PubMed:11274402). Interacts with IL1F7 (PubMed:20935647). Interaction with CSNK1G2 (PubMed:18794808). Interacts with PDPK1 (via PH domain) (PubMed:17327236). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation (PubMed:11387212). Interacts with USP15 (PubMed:21947082). Interacts with PPP5C; the interaction decreases SMAD3 phosphorylation and protein levels (PubMed:22781750). Interacts with LDLRAD4 (via the SMAD interaction motif) (PubMed:24627

EXTERNAL LINKS

SMAD3

Mutations

Mutation(s) distribution

Mutations table