SMAD2_PONAB
ID SMAD2_PONAB Reviewed; 467 AA.
AC Q5R7C0;
DT 12-JUN-2007, integrated into UniProtKB/Swiss-Prot.
DT 21-DEC-2004, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Mothers against decapentaplegic homolog 2;
DE Short=MAD homolog 2;
DE Short=Mothers against DPP homolog 2;
DE AltName: Full=SMAD family member 2;
DE Short=SMAD 2;
DE Short=Smad2;
GN Name=SMAD2;
OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9601;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RG The German cDNA consortium;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Receptor-regulated SMAD (R-SMAD) that is an intracellular
CC signal transducer and transcriptional modulator activated by TGF-beta
CC (transforming growth factor) and activin type 1 receptor kinases. Binds
CC the TRE element in the promoter region of many genes that are regulated
CC by TGF-beta and, on formation of the SMAD2/SMAD4 complex, activates
CC transcription. May act as a tumor suppressor in colorectal carcinoma.
CC Positively regulates PDPK1 kinase activity by stimulating its
CC dissociation from the 14-3-3 protein YWHAQ which acts as a negative
CC regulator (By similarity). {ECO:0000250|UniProtKB:Q15796,
CC ECO:0000250|UniProtKB:Q62432}.
CC -!- SUBUNIT: Monomer; in the absence of TGF-beta (By similarity).
CC Heterodimer; in the presence of TGF-beta (By similarity). Forms a
CC heterodimer with co-SMAD, SMAD4, in the nucleus to form the
CC transactivation complex SMAD2/SMAD4 (By similarity). Found in a complex
CC with SMAD3 and TRIM33 upon addition of TGF-beta (By similarity).
CC Identified in a complex that contains at least ZNF451, SMAD2, SMAD3 and
CC SMAD4 (By similarity). Interacts (via the MH2 domain) with ZFYVE9; may
CC form trimers with the SMAD4 co-SMAD (By similarity). Interacts with
CC TAZ/WWRT1 (By similarity). Interacts with FOXH1 (By similarity).
CC Interacts with SNW1 (By similarity). Interacts with CREB-binding
CC protein (CBP) and EP300 (By similarity). Interacts with SNON (By
CC similarity). Interacts with ALK4/ACVR1B (By similarity). Interacts with
CC SKOR1 (By similarity). Interacts with SKOR2 (By similarity). Interacts
CC with PRDM16 (By similarity). Interacts (via MH2 domain) with LEMD3 (By
CC similarity). Interacts with RBPMS (By similarity). Interacts with WWP1.
CC Interacts (dephosphorylated form, via the MH1 and MH2 domains) with
CC RANBP3 (via its C-terminal R domain); the interaction results in the
CC export of dephosphorylated SMAD3 out of the nucleus and termination of
CC the TGF-beta signaling (By similarity). Interacts with PDPK1 (via PH
CC domain) (By similarity). Interacts with DAB2; the interactions are
CC enhanced upon TGF-beta stimulation (By similarity). Interacts with
CC USP15 (By similarity). Interacts with PPP5C (By similarity). Interacts
CC with LDLRAD4 (via the SMAD interaction motif) (By similarity).
CC Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif)
CC (By similarity). Interacts with ZFHX3 (By similarity). Interacts with
CC ZNF451 (By similarity). Interacts with SMURF2 when phosphorylated on
CC Ser-465/467 (By similarity). Interacts with PPM1A (By similarity).
CC Interacts with TGF-beta (By similarity). Interacts with TGFBR1 (By
CC similarity). Interacts with TGIF (By similarity). Interacts with SMAD3
CC and TRIM33 (By similarity). Interacts with ZNF580 (By similarity).
CC Interacts with NEDD4L in response to TGF-beta (By similarity).
CC Interacts with HGS (By similarity). Interacts with AIP1 (By
CC similarity). Interacts with WWP1 (By similarity). Interacts with PML
CC (By similarity). Interacts weakly with ZNF8 (By similarity). Interacts
CC (when phosphorylated) with RNF111; RNF111 acts as an enhancer of the
CC transcriptional responses by mediating ubiquitination and degradation
CC of SMAD2 inhibitors (By similarity). Interacts with YAP1 (when
CC phosphorylated at 'Ser-55') (By similarity).
CC {ECO:0000250|UniProtKB:Q15796, ECO:0000250|UniProtKB:Q62432}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q15796}. Nucleus
CC {ECO:0000250|UniProtKB:Q15796}. Note=Cytoplasmic and nuclear in the
CC absence of TGF-beta (By similarity). On TGF-beta stimulation, migrates
CC to the nucleus when complexed with SMAD4 (By similarity). On
CC dephosphorylation by phosphatase PPM1A, released from the SMAD2/SMAD4
CC complex, and exported out of the nucleus by interaction with RANBP1 (By
CC similarity). Localized mainly to the nucleus in the early stages of
CC embryo development with expression becoming evident in the cytoplasm at
CC the blastocyst and epiblast stages (By similarity).
CC {ECO:0000250|UniProtKB:Q15796, ECO:0000250|UniProtKB:Q62432}.
CC -!- PTM: In response to TGF-beta, phosphorylated on the C-terminal SXS
CC motif by TGF-beta and activin type 1 receptor kinases, phosphorylation
CC declines progressively in a KMT5A-dependent manner. Phosphorylation in
CC this motif is required for interaction with a number of proteins
CC including SMURF2, SNON and SMAD4 in response to TGF-beta.
CC Dephosphorylated in this motif by PPM1A leading to disruption of the
CC SMAD2/3-SMAD4 complex, nuclear export and termination of the TGF-beta
CC signaling. In response to decorin, the naturally occurring inhibitor of
CC TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated
CC by MAPK3 upon EGF stimulation; which increases transcriptional activity
CC and stability, and is blocked by calmodulin. Phosphorylated by PDPK1
CC (By similarity). {ECO:0000250|UniProtKB:Q15796}.
CC -!- PTM: Acetylated on Lys-19 by coactivators in response to TGF-beta
CC signaling, which increases transcriptional activity.
CC {ECO:0000250|UniProtKB:Q15796}.
CC -!- PTM: In response to TGF-beta, ubiquitinated by NEDD4L; which promotes
CC its degradation. Monoubiquitinated, leading to prevent DNA-binding (By
CC similarity). Deubiquitination by USP15 alleviates inhibition and
CC promotes activation of TGF-beta target genes (By similarity).
CC Ubiquitinated by RNF111, leading to its degradation: only SMAD2
CC proteins that are 'in use' are targeted by RNF111, RNF111 playing a key
CC role in activating SMAD2 and regulating its turnover (By similarity).
CC {ECO:0000250|UniProtKB:Q15796, ECO:0000250|UniProtKB:Q62432}.
CC -!- SIMILARITY: Belongs to the dwarfin/SMAD family. {ECO:0000305}.
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DR EMBL; CR860198; CAH92340.1; -; mRNA.
DR RefSeq; NP_001126376.1; NM_001132904.2.
DR AlphaFoldDB; Q5R7C0; -.
DR SMR; Q5R7C0; -.
DR STRING; 9601.ENSPPYP00000010275; -.
DR ABCD; Q5R7C0; 1 sequenced antibody.
DR GeneID; 100173357; -.
DR KEGG; pon:100173357; -.
DR CTD; 4087; -.
DR eggNOG; KOG3701; Eukaryota.
DR InParanoid; Q5R7C0; -.
DR Proteomes; UP000001595; Unplaced.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005667; C:transcription regulator complex; ISS:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; ISS:UniProtKB.
DR GO; GO:0009952; P:anterior/posterior pattern specification; ISS:UniProtKB.
DR GO; GO:0045165; P:cell fate commitment; ISS:UniProtKB.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0001707; P:mesoderm formation; ISS:UniProtKB.
DR GO; GO:0048340; P:paraxial mesoderm morphogenesis; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0051098; P:regulation of binding; ISS:UniProtKB.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; ISS:UniProtKB.
DR Gene3D; 2.60.200.10; -; 1.
DR Gene3D; 3.90.520.10; -; 1.
DR InterPro; IPR013790; Dwarfin.
DR InterPro; IPR003619; MAD_homology1_Dwarfin-type.
DR InterPro; IPR013019; MAD_homology_MH1.
DR InterPro; IPR017855; SMAD-like_dom_sf.
DR InterPro; IPR001132; SMAD_dom_Dwarfin-type.
DR InterPro; IPR008984; SMAD_FHA_dom_sf.
DR InterPro; IPR036578; SMAD_MH1_sf.
DR PANTHER; PTHR13703; PTHR13703; 1.
DR Pfam; PF03165; MH1; 1.
DR Pfam; PF03166; MH2; 1.
DR SMART; SM00523; DWA; 1.
DR SMART; SM00524; DWB; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF56366; SSF56366; 1.
DR PROSITE; PS51075; MH1; 1.
DR PROSITE; PS51076; MH2; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Cytoplasm; DNA-binding; Metal-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation; Ubl conjugation; Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT CHAIN 2..467
FT /note="Mothers against decapentaplegic homolog 2"
FT /id="PRO_0000290339"
FT DOMAIN 10..176
FT /note="MH1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00438"
FT DOMAIN 274..467
FT /note="MH2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00439"
FT REGION 207..251
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 221..225
FT /note="PY-motif"
FT /evidence="ECO:0000250"
FT COMPBIAS 229..251
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 74
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 149
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 161
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT BINDING 166
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT MOD_RES 8
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT MOD_RES 19
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT MOD_RES 220
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT MOD_RES 240
FT /note="Phosphoserine; by CAMK2"
FT /evidence="ECO:0000250|UniProtKB:Q15796,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 245
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT MOD_RES 250
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT MOD_RES 255
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15796"
FT MOD_RES 458
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15796,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 460
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15796,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 464
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15796,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 465
FT /note="Phosphoserine; by TGFBR1"
FT /evidence="ECO:0000250|UniProtKB:Q15796,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
FT MOD_RES 467
FT /note="Phosphoserine; by TGFBR1"
FT /evidence="ECO:0000250|UniProtKB:Q15796,
FT ECO:0000255|PROSITE-ProRule:PRU00439"
SQ SEQUENCE 467 AA; 52307 MW; A343DE25DC0C8061 CRC64;
MSSILPFTPP VVKRLLGWKK SAGGSGGAGG GEQNGQEEKW CEKAVKSLVK KLKKTGRLDE
LEKAITTQNC NTKCVTIPST CSEIWGLSTP NTIDQWDTTG LYSFSEQTRS LDGRLQVSHR
KGLPHVIYCR LWRWPDLHSH HELKAIENCE YAFNLKEDEV CVNPYHYQRV ETPVLPPVLV
PRHTEILTEL PPLDDYTHSI PENTNFPAGI EPQSNYIPET PPPGYISEDG ETSDQQLNQS
MDTGSPAELS PTTLSPVNHS LDLQPVTYSE PAFWCSIAYY ELNQRVGETF HASQPSLTVD
GFTDPSNSER FCLGLLSNVN RNATVEMTRR HIGRGVRLYY IGGEVFAECL SDSAIFVQSP
NCNQRYGWHP ATVCKIPPGC NLKIFNNQEF AALLAQSVNQ GFEAVYQLTR MCTIRMSFVK
GWGAEYRRQT VTSTPCWIEL HLNGPLQWLD KVLTQMGSPS VRCSSMS
