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O70436

- SMAD2_RAT

UniProt

O70436 - SMAD2_RAT

Protein

Mothers against decapentaplegic homolog 2

Gene

Smad2

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 133 (01 Oct 2014)
      Sequence version 1 (01 Aug 1998)
      Previous versions | rss
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    Functioni

    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 SMAD2/SMAD4 complex, activates transcription. May act as a tumor suppressor in colorectal carcinoma. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator By similarity.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi74 – 741ZincBy similarity
    Metal bindingi149 – 1491ZincBy similarity
    Metal bindingi161 – 1611ZincBy similarity
    Metal bindingi166 – 1661ZincBy similarity

    GO - Molecular functioni

    1. chromatin binding Source: Ensembl
    2. double-stranded DNA binding Source: UniProtKB
    3. metal ion binding Source: UniProtKB-KW
    4. protein binding Source: UniProtKB
    5. sequence-specific DNA binding transcription factor activity Source: InterPro
    6. transcription factor binding Source: UniProtKB
    7. transforming growth factor beta receptor, pathway-specific cytoplasmic mediator activity Source: Ensembl

    GO - Biological processi

    1. anterior/posterior pattern specification Source: UniProtKB
    2. cell fate commitment Source: UniProtKB
    3. common-partner SMAD protein phosphorylation Source: Ensembl
    4. developmental growth Source: Ensembl
    5. embryonic cranial skeleton morphogenesis Source: Ensembl
    6. embryonic foregut morphogenesis Source: Ensembl
    7. endoderm formation Source: Ensembl
    8. insulin secretion Source: Ensembl
    9. intracellular signal transduction Source: UniProtKB
    10. in utero embryonic development Source: Ensembl
    11. lung development Source: Ensembl
    12. mesoderm formation Source: UniProtKB
    13. negative regulation of cell proliferation Source: RGD
    14. negative regulation of transcription, DNA-templated Source: Ensembl
    15. nodal signaling pathway Source: Ensembl
    16. organ growth Source: Ensembl
    17. palate development Source: Ensembl
    18. pancreas development Source: Ensembl
    19. paraxial mesoderm morphogenesis Source: UniProtKB
    20. pericardium development Source: Ensembl
    21. positive regulation of BMP signaling pathway Source: Ensembl
    22. positive regulation of epithelial to mesenchymal transition Source: Ensembl
    23. positive regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry Source: Ensembl
    24. positive regulation of transcription, DNA-templated Source: UniProtKB
    25. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    26. post-embryonic development Source: Ensembl
    27. regulation of binding Source: UniProtKB
    28. regulation of transforming growth factor beta receptor signaling pathway Source: Ensembl
    29. response to cholesterol Source: Ensembl
    30. response to glucose Source: Ensembl
    31. signal transduction involved in regulation of gene expression Source: BHF-UCL
    32. SMAD protein complex assembly Source: Ensembl
    33. transcription, DNA-templated Source: UniProtKB-KW
    34. transforming growth factor beta receptor signaling pathway Source: UniProtKB
    35. ureteric bud development Source: Ensembl
    36. zygotic specification of dorsal/ventral axis Source: Ensembl

    Keywords - Biological processi

    Transcription, Transcription regulation

    Keywords - Ligandi

    DNA-binding, Metal-binding, Zinc

    Enzyme and pathway databases

    ReactomeiREACT_194628. Signaling by Activin.
    REACT_194629. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
    REACT_194639. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
    REACT_194641. Downregulation of TGF-beta receptor signaling.
    REACT_194651. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_194653. SMAD4 MH2 Domain Mutants in Cancer.
    REACT_194657. TGFBR1 KD Mutants in Cancer.
    REACT_194664. Signaling by NODAL.
    REACT_194677. TGF-beta receptor signaling activates SMADs.
    REACT_194682. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
    REACT_228003. Transcriptional regulation of pluripotent stem cells.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Mothers against decapentaplegic homolog 2
    Short name:
    MAD homolog 2
    Short name:
    Mothers against DPP homolog 2
    Alternative name(s):
    Mad-related protein 2
    SMAD family member 2
    Short name:
    SMAD 2
    Short name:
    Smad2
    Gene namesi
    Name:Smad2
    Synonyms:Madh2
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 18

    Organism-specific databases

    RGDi3031. Smad2.

    Subcellular locationi

    Cytoplasm By similarity. Nucleus By similarity
    Note: Cytoplasmic and nuclear in the absence of TGF-beta. On TGF-beta stimulation, migrates to the nucleus when complexed with SMAD4. On dephosphorylation by phosphatase PPM1A, released from the SMAD2/SMAD4 complex, and exported out of the nucleus by interaction with RANBP1 By similarity.By similarity

    GO - Cellular componenti

    1. activin responsive factor complex Source: Ensembl
    2. cytoplasm Source: RGD
    3. nucleus Source: UniProtKB
    4. protein complex Source: RGD
    5. SMAD protein complex Source: Ensembl
    6. transcription factor complex Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 467466Mothers against decapentaplegic homolog 2PRO_0000090854Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylserineBy similarity
    Modified residuei8 – 81PhosphothreonineBy similarity
    Modified residuei19 – 191N6-acetyllysineBy similarity
    Modified residuei240 – 2401Phosphoserine; by CAMK2PROSITE-ProRule annotation
    Modified residuei458 – 4581PhosphoserinePROSITE-ProRule annotation
    Modified residuei460 – 4601PhosphoserinePROSITE-ProRule annotation
    Modified residuei464 – 4641PhosphoserinePROSITE-ProRule annotation
    Modified residuei465 – 4651Phosphoserine; by TGFBR1PROSITE-ProRule annotation
    Modified residuei467 – 4671Phosphoserine; by TGFBR1PROSITE-ProRule annotation

    Post-translational modificationi

    In response to TGF-beta, phosphorylated on the C-terminal SXS motif by TGF-beta and activin type 1 receptor kinases, phosphorylation declines progressively in a SETD8-dependent manner. Phosphorylation in this motif is required for interaction with a number of proteins including SMURF2, SNON and SMAD4 in response to TGF-beta. Dephosphorylated in this motif by PPM1A leading to disruption of the SMAD2/3-SMAD4 complex, nuclear export and termination of the TGF-beta signaling. In response to decorin, the naturally occurring inhibitor of TGF-beta signaling, phosphorylated on Ser-240 by CaMK2. Phosphorylated by MAPK3 upon EGF stimulation; which increases transcriptional activity and stability, and is blocked by calmodulin. Phosphorylated by PDPK1 By similarity.By similarity
    In response to TGF-beta, ubiquitinated by NEDD4L; which promotes its degradation. Monoubiquitinated, leading to prevent DNA-binding. Deubiquitination by USP15 alleviates inhibition and promotes activation of TGF-beta target genes By similarity.By similarity
    Acetylated on Lys-19 by coactivators in response to TGF-beta signaling, which increases transcriptional activity.By similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiO70436.
    PRIDEiO70436.

    PTM databases

    PhosphoSiteiO70436.

    Expressioni

    Gene expression databases

    GenevestigatoriO70436.

    Interactioni

    Subunit structurei

    Momomer; the absence of TGF-beta. Interacts with ZNF580. Heterodimer; in the presence of TGF-beta. Forms a heterodimer with co-SMAD, SMAD4, in the nucleus to form the transactivation complex SMAD2/SMAD4. Found in a complex with ACVR1B, SMAD3 and TRIM33 upon addition of TGF-beta. Interacts with SMAD3 and TRIM33. Interacts (via the MH2 domain) with ZFYVE9; may form trimers with the SMAD4 co-SMAD. Interacts with FOXH1, homeobox protein TGIF, PEBP2-alpha subunit, CREB-binding protein (CBP), EP300, SKI and SNW1. Interacts with SNON; when phosphorylated at Ser-465/467. Interacts (via PY-motif) with SMURF2. Interacts with AIP1 and HGS. Interacts with NEDD4L in response to TGF-beta. Interacts with SKOR1 and SKOR2. Interacts with PRDM16. Interacts (via MH2 domain) with LEMD3. Interacts with RBPMS. Interacts with WWP1. 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. Interacts with PML. Interacts with PDPK1 (via PH domain). Interacts with DAB2; the interactions are enhanced upon TGF-beta stimulation. Interacts with USP15. Interacts with PPP5C. Interacts with LDLRAD4 (via the SMAD interaction motif). Interacts (via MH2 domain) with PMEPA1 (via the SMAD interaction motif) By similarity.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Akt1P471962EBI-7948047,EBI-7204362

    Protein-protein interaction databases

    BioGridi248011. 2 interactions.
    IntActiO70436. 1 interaction.
    MINTiMINT-2739674.

    Structurei

    3D structure databases

    ProteinModelPortaliO70436.
    SMRiO70436. Positions 7-172, 265-467.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini10 – 176167MH1PROSITE-ProRule annotationAdd
    BLAST
    Domaini274 – 467194MH2PROSITE-ProRule annotationAdd
    BLAST

    Motif

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Motifi221 – 2255PY-motifBy similarity

    Sequence similaritiesi

    Belongs to the dwarfin/SMAD family.Curated
    Contains 1 MH1 (MAD homology 1) domain.PROSITE-ProRule annotation
    Contains 1 MH2 (MAD homology 2) domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiNOG320700.
    GeneTreeiENSGT00600000084186.
    HOGENOMiHOG000286018.
    HOVERGENiHBG053353.
    InParanoidiO70436.
    KOiK04500.
    OMAiMNQSMDT.
    OrthoDBiEOG7W1540.
    PhylomeDBiO70436.
    TreeFamiTF314923.

    Family and domain databases

    Gene3Di2.60.200.10. 1 hit.
    3.90.520.10. 1 hit.
    InterProiIPR013790. Dwarfin.
    IPR003619. MAD_homology1_Dwarfin-type.
    IPR013019. MAD_homology_MH1.
    IPR017855. SMAD_dom-like.
    IPR001132. SMAD_dom_Dwarfin-type.
    IPR008984. SMAD_FHA_domain.
    [Graphical view]
    PANTHERiPTHR13703. PTHR13703. 1 hit.
    PfamiPF03165. MH1. 1 hit.
    PF03166. MH2. 1 hit.
    [Graphical view]
    SMARTiSM00523. DWA. 1 hit.
    SM00524. DWB. 1 hit.
    [Graphical view]
    SUPFAMiSSF49879. SSF49879. 1 hit.
    SSF56366. SSF56366. 2 hits.
    PROSITEiPS51075. MH1. 1 hit.
    PS51076. MH2. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    O70436-1 [UniParc]FASTAAdd to Basket

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    MSSILPFTPP VVKRLLGWKK SAGGSGGAGG GEQNGQEEKW CEKAVKSLVK    50
    KLKKTGRLDE LEKAITTQNC NTKCVTIPST CSEIWGLSTA NTVDQWDTTG 100
    LYSFSEQTRS LDGRLQVSHR KGLPHVIYCR LWRWPDLHSH HELKAIENCE 150
    YAFSLKKDEV CVNPYHYQRV ETPVLPPVLV PRHTEILTEL PPLDDYTHSI 200
    PENTNFPAGI EPQSNYIPET PPPGYISEDG ETSDQQLNQS MDTGSPAELS 250
    PTTLSPVNHS LDLQPVTYSE PAFWCSIAYY ELNQRVGETF HASQPSLTVD 300
    GFTDPSNSER FCLGLLSNVN RNATVEMTRR HIGRGVRLYY IGGEVFAECL 350
    SDSAIFVQSP NCNQRYGWHP ATVCKIPPGC NLKIFNNQEF AALLAQSVNQ 400
    GFEAVYQLTR MCTIRMSFVK GWGAEYRRQT VTSTPCWIEL HLNGPLQWLD 450
    KVLTQMGSPS VRCSSMS 467
    Length:467
    Mass (Da):52,239
    Last modified:August 1, 1998 - v1
    Checksum:i3A775444411F6619
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB017912 mRNA. Translation: BAA33453.1.
    AF056001 mRNA. Translation: AAC12780.1.
    AB010147 mRNA. Translation: BAA81909.1.
    BC127497 mRNA. Translation: AAI27498.1.
    RefSeqiNP_001264379.1. NM_001277450.1.
    NP_062064.1. NM_019191.2.
    UniGeneiRn.2755.

    Genome annotation databases

    EnsembliENSRNOT00000046847; ENSRNOP00000048329; ENSRNOG00000018140.
    GeneIDi29357.
    KEGGirno:29357.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AB017912 mRNA. Translation: BAA33453.1 .
    AF056001 mRNA. Translation: AAC12780.1 .
    AB010147 mRNA. Translation: BAA81909.1 .
    BC127497 mRNA. Translation: AAI27498.1 .
    RefSeqi NP_001264379.1. NM_001277450.1.
    NP_062064.1. NM_019191.2.
    UniGenei Rn.2755.

    3D structure databases

    ProteinModelPortali O70436.
    SMRi O70436. Positions 7-172, 265-467.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 248011. 2 interactions.
    IntActi O70436. 1 interaction.
    MINTi MINT-2739674.

    PTM databases

    PhosphoSitei O70436.

    Proteomic databases

    PaxDbi O70436.
    PRIDEi O70436.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000046847 ; ENSRNOP00000048329 ; ENSRNOG00000018140 .
    GeneIDi 29357.
    KEGGi rno:29357.

    Organism-specific databases

    CTDi 4087.
    RGDi 3031. Smad2.

    Phylogenomic databases

    eggNOGi NOG320700.
    GeneTreei ENSGT00600000084186.
    HOGENOMi HOG000286018.
    HOVERGENi HBG053353.
    InParanoidi O70436.
    KOi K04500.
    OMAi MNQSMDT.
    OrthoDBi EOG7W1540.
    PhylomeDBi O70436.
    TreeFami TF314923.

    Enzyme and pathway databases

    Reactomei REACT_194628. Signaling by Activin.
    REACT_194629. SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription.
    REACT_194639. Downregulation of SMAD2/3:SMAD4 transcriptional activity.
    REACT_194641. Downregulation of TGF-beta receptor signaling.
    REACT_194651. SMAD2/3 MH2 Domain Mutants in Cancer.
    REACT_194653. SMAD4 MH2 Domain Mutants in Cancer.
    REACT_194657. TGFBR1 KD Mutants in Cancer.
    REACT_194664. Signaling by NODAL.
    REACT_194677. TGF-beta receptor signaling activates SMADs.
    REACT_194682. SMAD2/3 Phosphorylation Motif Mutants in Cancer.
    REACT_228003. Transcriptional regulation of pluripotent stem cells.

    Miscellaneous databases

    NextBioi 608870.
    PROi O70436.

    Gene expression databases

    Genevestigatori O70436.

    Family and domain databases

    Gene3Di 2.60.200.10. 1 hit.
    3.90.520.10. 1 hit.
    InterProi IPR013790. Dwarfin.
    IPR003619. MAD_homology1_Dwarfin-type.
    IPR013019. MAD_homology_MH1.
    IPR017855. SMAD_dom-like.
    IPR001132. SMAD_dom_Dwarfin-type.
    IPR008984. SMAD_FHA_domain.
    [Graphical view ]
    PANTHERi PTHR13703. PTHR13703. 1 hit.
    Pfami PF03165. MH1. 1 hit.
    PF03166. MH2. 1 hit.
    [Graphical view ]
    SMARTi SM00523. DWA. 1 hit.
    SM00524. DWB. 1 hit.
    [Graphical view ]
    SUPFAMi SSF49879. SSF49879. 1 hit.
    SSF56366. SSF56366. 2 hits.
    PROSITEi PS51075. MH1. 1 hit.
    PS51076. MH2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Involvement of Smad proteins in the differentiation of pancreatic AR42J cells induced by activin A."
      Zhang Y.-Q., Kanzaki M., Furukawa M., Shibata H., Ozeki M., Kojima I.
      Diabetologia 42:719-727(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Strain: Sprague-Dawley.
      Tissue: Brain.
    2. "cDNA cloning and chromosomal mapping of rat Smad2 and Smad4 and their expression in cultured rat articular chondrocytes."
      Osaki M., Tsukazaki T., Ono N., Yonekura A., Hirota Y., Miyazaki Y., Shindo H., Sonta S., Yamashita S.
      Endocr. J. 46:695-701(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    3. "Molecular cloning of rat Smad2 gene."
      Miyakita A., Okuno S., Watanabe T.K., Oga K., Tsuji A., Hishigaki H., Kato S., Sano A., Suto T., Nakagawa K., Nakahara Y., Haraguchi N., Higashi K.
      Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Tissue: Testis.
    4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Brain.

    Entry informationi

    Entry nameiSMAD2_RAT
    AccessioniPrimary (citable) accession number: O70436
    Secondary accession number(s): A0JPM1
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: April 27, 2001
    Last sequence update: August 1, 1998
    Last modified: October 1, 2014
    This is version 133 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3