Q13485 (SMAD4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mothers against decapentaplegic homolog 4
Short name=MAD homolog 4
Short name=Mothers against DPP homolog 4

Alternative name(s):
Deletion target in pancreatic carcinoma 4
SMAD family member 4
Short name=SMAD 4
Short name=Smad4
Short name=hSMAD4

Gene names

Name:	SMAD4
Synonyms:	DPC4, MADH4

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	552 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. Ref.7 Ref.20
Subunit structure	Interacts with CITED2 By similarity. Monomer; in the absence of TGF-beta activation. Heterodimer; on TGF-beta activation. Composed of two molecules of a C-terminally phosphorylated R-SMAD molecule, SMAD2 or SMAD3, and one molecule of SMAD4 to form the transcriptional active SMAD2/SMAD3-SMAD4 complex. Found in a ternary complex composed of SMAD4, STK11/LKB1 and STK11IP. Interacts with ATF2, COPS5, DACH1, MSG1, SKI, STK11/LKB1, STK11IP and TRIM33. Interacts with ZNF423; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with ZNF521; the interaction takes place in response to BMP2 leading to activation of transcription of BMP target genes. Interacts with USP9X. Interacts (via the MH1 and MH2 domains) with RBPMS. Interacts with WWTR1 (via coiled-coil domain). Component of the multimeric complex SMAD3/SMAD4/JUN/FOS which forms at the AP1 promoter site; required for syngernistic transcriptional activity in response to TGF-beta. Interacts with CITED1. Interacts with PDPK1 (via PH domain) By similarity. Interacts with VPS39; this interaction affects heterodimer formation with SMAD3, but not with SMAD2, and leads to inhibition of SMAD3-dependent transcription activation. Interactions with VPS39 and SMAD2 may be mutually exclusive. Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.28 Ref.29
Subcellular location	Cytoplasm. Nucleus. Note: Cytoplasmic in the absence of ligand. Migrates to the nucleus when complexed with R-SMAD. PDPK1 prevents its nuclear translocation in response to TGF-beta. Ref.18 Ref.20
Domain	The MH1 domain is required for DNA binding. Ref.11 The MH2 domain is required for both homomeric and heteromeric interactions and for transcriptional regulation. Sufficient for nuclear import. Ref.11
Post-translational modification	Phosphorylated by PDPK1. Ref.20 Monoubiquitinated on Lys-519 by E3 ubiquitin-protein ligase TRIM33. Monoubiquitination hampers its ability to form a stable complex with activated SMAD2/3 resulting in inhibition of TGF-beta/BMP signaling cascade. Deubiqitination by USP9X restores its competence to mediate TGF-beta signaling.
Involvement in disease	Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. Note: The gene represented in this entry may be involved in disease pathogenesis. Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.30 Ref.31 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.32 Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note: The disease may be caused by mutations affecting the gene represented in this entry. Primary pulmonary hypertension (PPH1) [MIM:178600]: A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. Note: The disease may be caused by mutations affecting the gene represented in this entry. Ref.25 Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.34 Ref.35
Sequence similarities	Belongs to the dwarfin/SMAD family. Contains 1 MH1 (MAD homology 1) domain. Contains 1 MH2 (MAD homology 2) domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	DNA-binding Metal-binding Zinc
PTM	Acetylation Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	BMP signaling pathway Inferred from direct assay Ref.7. Source: BHF-UCL SMAD protein complex assembly Inferred from direct assay PubMed 10823886. Source: BHF-UCL SMAD protein signal transduction Inferred from direct assay Ref.9PubMed 9732876. Source: BHF-UCL branching involved in ureteric bud morphogenesis Inferred from electronic annotation. Source: Compara cell proliferation Inferred from electronic annotation. Source: Compara developmental growth Inferred from electronic annotation. Source: Compara endoderm development Inferred from electronic annotation. Source: Compara formation of anatomical boundary Inferred from electronic annotation. Source: Compara gastrulation with mouth forming second Inferred from electronic annotation. Source: Compara in utero embryonic development Inferred from electronic annotation. Source: Compara mesoderm development Inferred from electronic annotation. Source: Compara metanephric mesenchyme morphogenesis Inferred from electronic annotation. Source: Compara negative regulation of cell death Inferred from electronic annotation. Source: Compara negative regulation of cell growth Inferred from direct assay Ref.2. Source: BHF-UCL negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of protein catabolic process Inferred from mutant phenotype PubMed 20097766. Source: BHF-UCL negative regulation of transcription from RNA polymerase II promoter Traceable author statement. Source: Reactome nephrogenic mesenchyme morphogenesis Inferred from electronic annotation. Source: Compara neural crest cell differentiation Inferred from electronic annotation. Source: Compara neuron fate commitment Inferred from electronic annotation. Source: Compara palate development Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of BMP signaling pathway Inferred from mutant phenotype PubMed 19366699. Source: BHF-UCL positive regulation of SMAD protein import into nucleus Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of epithelial to mesenchymal transition Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of pathway-restricted SMAD protein phosphorylation Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 18832382. Source: UniProtKB positive regulation of transforming growth factor beta receptor signaling pathway Inferred from direct assay PubMed 19328798. Source: BHF-UCL regulation of binding Inferred from electronic annotation. Source: Compara regulation of hair follicle development Inferred from electronic annotation. Source: Compara regulation of transforming growth factor beta2 production Inferred from mutant phenotype PubMed 12411310. Source: BHF-UCL response to hypoxia Inferred from mutant phenotype PubMed 12411310. Source: BHF-UCL sebaceous gland development Inferred from electronic annotation. Source: Compara somite rostral/caudal axis specification Inferred from electronic annotation. Source: Compara transcription initiation from RNA polymerase II promoter Traceable author statement. Source: Reactome transforming growth factor beta receptor signaling pathway Inferred from direct assay Ref.7PubMed 9732876. Source: BHF-UCL
Cellular_component	SMAD protein complex Inferred from direct assay PubMed 18832382. Source: UniProtKB activin responsive factor complex Inferred from direct assay Ref.7. Source: BHF-UCL centrosome Inferred from direct assay. Source: HPA cytosol Traceable author statement. Source: Reactome
Molecular_function	chromatin binding Inferred from electronic annotation. Source: Compara core promoter proximal region sequence-specific DNA binding Inferred from direct assay PubMed 18832382. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW sequence-specific DNA binding transcription factor activity Inferred from electronic annotation. Source: Compara transforming growth factor beta receptor, common-partner cytoplasmic mediator activity Inferred from direct assay Ref.7. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
DACH1	Q9UI36	3	EBI-347263,EBI-347111
DLX4	Q92988	5	EBI-347263,EBI-1752755
FOXO3	O43524	4	EBI-347263,EBI-1644164
GATA2	P23769	2	EBI-347263,EBI-2806671
NLK	Q9UBE8	5	EBI-347263,EBI-366978
SKI	P12755	3	EBI-347263,EBI-347281
SMAD2	Q15796	12	EBI-347263,EBI-1040141
SMAD3	P84022	9	EBI-347263,EBI-347161
SP1	P08047	2	EBI-347263,EBI-298336
TRIM33	Q9UPN9	5	EBI-347263,EBI-2214398
UBE2I	P63279	3	EBI-347263,EBI-80168
USP9X	Q93008	2	EBI-347263,EBI-302524
Usp9x	P70398	4	EBI-347263,EBI-2214043	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 552

552

Mothers against decapentaplegic homolog 4

PRO_0000090861

Regions

Domain

18 – 142

125

MH1

Domain

323 – 552

230

MH2

Region

275 – 320

46

SAD

Compositional bias

451 – 466

16

Poly-Ala

Sites

Metal binding

71

1

Zinc By similarity

Metal binding

115

1

Zinc By similarity

Metal binding

127

1

Zinc By similarity

Metal binding

132

1

Zinc By similarity

Site

515

1

Necessary for heterotrimerization

Amino acid modifications

Modified residue

37

1

N6-acetyllysine Ref.23

Modified residue

428

1

N6-acetyllysine Ref.23

Modified residue

507

1

N6-acetyllysine Ref.23

Cross-link

519

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)

Natural variations

Natural variant

13

1

N → S. Ref.25

VAR_066870

Natural variant

101

1

W → G.
Corresponds to variant rs2229083 [ dbSNP | Ensembl ].

VAR_052022

Natural variant

130

1

P → S in a colorectal cancer sample; somatic mutation. Ref.33

VAR_036475

Natural variant

330

1

E → G in JPS. Ref.31

VAR_022833

Natural variant

351

1

D → N in a colorectal cancer sample; somatic mutation. Ref.33

VAR_036476

Natural variant

352

1

G → R in JP/HHT and JPS. Ref.31 Ref.32

VAR_019571

Natural variant

361

1

R → C in JPS. Ref.30

VAR_019572

Natural variant

361

1

R → H in a colorectal cancer sample; somatic mutation. Ref.33

VAR_036477

Natural variant

386

1

G → D in JP/HHT. Ref.32
Corresponds to variant rs28936393 [ dbSNP | Ensembl ].

VAR_019573

Natural variant

493

1

D → H in pancreatic carcinoma. Ref.1
Corresponds to variant rs28936392 [ dbSNP | Ensembl ].

VAR_011380

Natural variant

500

1

I → M in MYHRS. Ref.35

VAR_067602

Natural variant

500

1

I → T in MYHRS; there is an enhanced levels of SMAD4 protein with lower levels of ubiquitinated SMAD4 fibroblasts compared to controls suggesting stabilization of the mutant protein; 8-fold increase in phosphorylated SMAD2 and SMAD3; 11-fold increase in phosphorylated SMAD1, SMAD5 and SMAD8 in cell nuclei compared to controls. Ref.34 Ref.35

VAR_067603

Natural variant

500

1

I → V in MYHRS. Ref.34 Ref.35

VAR_067604

Experimental info

Mutagenesis

416

1

R → S: No effect on heterotrimerization. Partially diminished transcriptional activation. Ref.28

Mutagenesis

496

1

R → S: No effect on heterotrimerization. Partially diminished transcriptional activation.

Mutagenesis

502

1

R → S: No effect on heterotrimerization. Greatly reduced transcriptional activation. Ref.28

Mutagenesis

515

1

R → S: Reduced heterotrimerization. Ref.28

Mutagenesis

519

1

K → R: Abolishes ubiquitination. Ref.22

Secondary structure

1

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552

Helix Strand Turn

Details...

Beta strand

288 – 291

4

Beta strand

321 – 330

10

Beta strand

333 – 342

10

Beta strand

346 – 353

8

Beta strand

359 – 363

5

Helix

364 – 366

3

Helix

374 – 380

7

Turn

381 – 385

5

Beta strand

387 – 392

6

Turn

393 – 395

3

Beta strand

396 – 401

6

Beta strand

403 – 405

3

Beta strand

407 – 410

4

Helix

412 – 416

5

Turn

417 – 419

3

Beta strand

427 – 429

3

Beta strand

434 – 438

5

Helix

440 – 454

15

Turn

455 – 458

4

Helix

493 – 497

5

Beta strand

500 – 506

7

Helix

518 – 520

3

Beta strand

521 – 529

9

Helix

530 – 541

12

Sequences

	Sequence		Length	Mass (Da)
	Q13485 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: 7EE3C4647712DA90	FASTA	552	60,439
	10 20 30 40 50 60 MDNMSITNTP TSNDACLSIV HSLMCHRQGG ESETFAKRAI ESLVKKLKEK KDELDSLITA 70 80 90 100 110 120 ITTNGAHPSK CVTIQRTLDG RLQVAGRKGF PHVIYARLWR WPDLHKNELK HVKYCQYAFD 130 140 150 160 170 180 LKCDSVCVNP YHYERVVSPG IDLSGLTLQS NAPSSMMVKD EYVHDFEGQP SLSTEGHSIQ 190 200 210 220 230 240 TIQHPPSNRA STETYSTPAL LAPSESNATS TANFPNIPVA STSQPASILG GSHSEGLLQI 250 260 270 280 290 300 ASGPQPGQQQ NGFTGQPATY HHNSTTTWTG SRTAPYTPNL PHHQNGHLQH HPPMPPHPGH 310 320 330 340 350 360 YWPVHNELAF QPPISNHPAP EYWCSIAYFE MDVQVGETFK VPSSCPIVTV DGYVDPSGGD 370 380 390 400 410 420 RFCLGQLSNV HRTEAIERAR LHIGKGVQLE CKGEGDVWVR CLSDHAVFVQ SYYLDREAGR 430 440 450 460 470 480 APGDAVHKIY PSAYIKVFDL RQCHRQMQQQ AATAQAAAAA QAAAVAGNIP GPGSVGGIAP 490 500 510 520 530 540 AISLSAAAGI GVDDLRRLCI LRMSFVKGWG PDYPRQSIKE TPCWIEIHLH RALQLLDEVL 550 HTMPIADPQP LD

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1." Hahn S.A., Schutte M., Shamsul Hoque A.T.M., Moskaluk C.A., da Costa L.T., Rozenblum E., Weinstein C.L., Fischer A., Yeo C.J., Hruban R.H., Kern S.E. Science 271:350-353(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], VARIANT PANCREATIC CARCINOMA HIS-493. Tissue: Fetal brain.
[2]	"Receptor-associated Mad homologues synergize as effectors of the TGF-beta response." Zhang Y., Feng X.-H., Wu R.-Y., Derynck R. Nature 383:168-172(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Placenta.
[3]	"Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma." Moskaluk C.A., Hruban R.H., Schutte M., Lietman A.S., Smyrk T., Fusaro L., Fusaro R., Lynch J., Yeo C.J., Jackson C.E., Lynch H.T., Kern S.E. Diagn. Mol. Pathol. 6:85-90(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: Muscle.
[7]	"Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes." Liu F., Pouponnot C., Massague J. Genes Dev. 11:3157-3167(1997) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[8]	"Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors." Kawabata M., Inoue H., Hanyu A., Imamura T., Miyazono K. EMBO J. 17:4056-4065(1998) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT.
[9]	"Transcriptional activating activity of Smad4: roles of SMAD hetero-oligomerization and enhancement by an associating transactivator." Shioda T., Lechleider R.J., Dunwoodie S.L., Li H., Yahata T., de Caestecker M.P., Fenner M.H., Roberts A.B., Isselbacher K.J. Proc. Natl. Acad. Sci. U.S.A. 95:9785-9790(1998) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CITED1.
[10]	"OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways." Hata A., Seoane J., Lagna G., Montalvo E., Hemmati-Brivanlou A., Massague J. Cell 100:229-240(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ZNF423.
[11]	"The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain." de Caestecker M.P., Yahata T., Wang D., Parks W.T., Huang S., Hill C.S., Shioda T., Roberts A.B., Lechleider R.J. J. Biol. Chem. 275:2115-2122(2000) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION OF SAD DOMAIN.
[12]	"LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1." Smith D.P., Rayter S.I., Niederlander C., Spicer J., Jones C.M., Ashworth A. Hum. Mol. Genet. 10:2869-2877(2001) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION IN A TERNARY COMPLEX COMPOSED OF STK11/LKB1 AND STK11IP, INTERACTION WITH STK11/LKB1 AND STK11IP.
[13]	"Jab1 antagonizes TGF-beta signaling by inducing Smad4 degradation." Wan M., Cao X., Wu Y., Bai S., Wu L., Shi X., Wang N., Cao X. EMBO Rep. 3:171-176(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH COPS5.
[14]	"TLP, a novel modulator of TGF-beta signaling, has opposite effects on Smad2- and Smad3-dependent signaling." Felici A., Wurthner J.U., Parks W.T., Giam L.R., Reiss M., Karpova T.S., McNally J.G., Roberts A.B. EMBO J. 22:4465-4477(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH VPS39.
[15]	"DACH1 inhibits transforming growth factor-beta signaling through binding Smad4." Wu K., Yang Y., Wang C., Davoli M.A., D'Amico M., Li A., Cveklova K., Kozmik Z., Lisanti M.P., Russell R.G., Cvekl A., Pestell R.G. J. Biol. Chem. 278:51673-51684(2003) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DACH1.
[16]	"Early hematopoietic zinc finger protein (EHZF), the human homolog to mouse Evi3, is highly expressed in primitive human hematopoietic cells." Bond H.M., Mesuraca M., Carbone E., Bonelli P., Agosti V., Amodio N., De Rosa G., Di Nicola M., Gianni A.M., Moore M.A., Hata A., Grieco M., Morrone G., Venuta S. Blood 103:2062-2070(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH ZNF521.
[17]	"Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase." Dupont S., Zacchigna L., Cordenonsi M., Soligo S., Adorno M., Rugge M., Piccolo S. Cell 121:87-99(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TRIM33.
[18]	"Nuclear targeting of transforming growth factor-beta-activated Smad complexes." Chen H.B., Rud J.G., Lin K., Xu L. J. Biol. Chem. 280:21329-21336(2005) [PubMed] [Europe PMC] [Abstract] Cited for: SUBUNIT, SUBCELLULAR LOCATION.
[19]	"Potentiation of Smad-mediated transcriptional activation by the RNA-binding protein RBPMS." Sun Y., Ding L., Zhang H., Han J., Yang X., Yan J., Zhu Y., Li J., Song H., Ye Q. Nucleic Acids Res. 34:6314-6326(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH RBPMS.
[20]	"3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins." Seong H.A., Jung H., Kim K.T., Ha H. J. Biol. Chem. 282:12272-12289(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION BY PDPK1, INTERACTION WITH PDPK1.
[21]	"TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal." Varelas X., Sakuma R., Samavarchi-Tehrani P., Peerani R., Rao B.M., Dembowy J., Yaffe M.B., Zandstra P.W., Wrana J.L. Nat. Cell Biol. 10:837-848(2008) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH WWTR1.
[22]	"FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination." Dupont S., Mamidi A., Cordenonsi M., Montagner M., Zacchigna L., Adorno M., Martello G., Stinchfield M.J., Soligo S., Morsut L., Inui M., Moro S., Modena N., Argenton F., Newfeld S.J., Piccolo S. Cell 136:123-135(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH USP9X, UBIQUITINATION, MUTAGENESIS OF LYS-519.
[23]	"Lysine acetylation targets protein complexes and co-regulates major cellular functions." Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M. Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract] Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-37; LYS-428 AND LYS-507, MASS SPECTROMETRY.
[24]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[25]	"Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension." Nasim M.T., Ogo T., Ahmed M., Randall R., Chowdhury H.M., Snape K.M., Bradshaw T.Y., Southgate L., Lee G.J., Jackson I., Lord G.M., Gibbs J.S., Wilkins M.R., Ohta-Ogo K., Nakamura K., Girerd B., Coulet F., Soubrier F. , Humbert M., Morrell N.W., Trembath R.C., Machado R.D. Hum. Mutat. 32:1385-1389(2011) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN PPH1, VARIANT SER-13.
[26]	"A structural basis for mutational inactivation of the tumour suppressor Smad4." Shi Y., Hata A., Lo R.S., Massague J., Pavletich N.P. Nature 388:87-93(1997) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 319-543.
[27]	"Crystal structure of a transcriptionally active Smad4 fragment." Qin B., Lam S.S., Lin K. Structure 7:1493-1503(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 285-552.
[28]	"The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization." Chacko B.M., Qin B., Correia J.J., Lam S.S., de Caestecker M.P., Lin K. Nat. Struct. Biol. 8:248-253(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3 ANGSTROMS) OF 273-552 OF WILD TYPE AND MUTANTS ARG-416; ARG-502 AND ARG-515 IN COMPLEX WITH SMAD3, SUBUNIT, MUTAGENESIS OF ARG-416; ARG-502 AND ARG-515.
[29]	"Structural basis of heteromeric smad protein assembly in TGF-beta signaling." Chacko B.M., Qin B.Y., Tiwari A., Shi G., Lam S., Hayward L.J., De Caestecker M., Lin K. Mol. Cell 15:813-823(2004) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 314-552 IN COMPLEX WITH SMAD2 OR SMAD3, SUBUNIT.
[30]	"Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases." Houlston R., Bevan S., Williams A., Young J., Dunlop M., Rozen P., Eng C., Markie D., Woodford-Richens K., Rodriguez-Bigas M.A., Leggett B., Neale K., Phillips R., Sheridan E., Hodgson S., Iwama T., Eccles D., Bodmer W., Tomlinson I. Hum. Mol. Genet. 7:1907-1912(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT JPS CYS-361.
[31]	"Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis." Sayed M.G., Ahmed A.F., Ringold J.R., Anderson M.E., Bair J.L., Mitros F.A., Lynch H.T., Tinley S.T., Petersen G.M., Giardiello F.M., Vogelstein B., Howe J.R. Ann. Surg. Oncol. 9:901-906(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS JPS GLY-330 AND ARG-352.
[32]	"A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)." Gallione C.J., Repetto G.M., Legius E., Rustgi A.K., Schelley S.L., Tejpar S., Mitchell G., Drouin E., Westermann C.J.J., Marchuk D.A. Lancet 363:852-859(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS JP/HHT ARG-352 AND ASP-386.
[33]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] SER-130; ASN-351 AND HIS-361.
[34]	"A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome." Caputo V., Cianetti L., Niceta M., Carta C., Ciolfi A., Bocchinfuso G., Carrani E., Dentici M.L., Biamino E., Belligni E., Garavelli L., Boccone L., Melis D., Andria G., Gelb B.D., Stella L., Silengo M., Dallapiccola B., Tartaglia M. Am. J. Hum. Genet. 90:161-169(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS MYHRS THR-500 AND VAL-500.
[35]	"Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome." Le Goff C., Mahaut C., Abhyankar A., Le Goff W., Serre V., Afenjar A., Destree A., di Rocco M., Heron D., Jacquemont S., Marlin S., Simon M., Tolmie J., Verloes A., Casanova J.L., Munnich A., Cormier-Daire V. Nat. Genet. 44:85-88(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS MYHRS MET-500; THR-500 AND VAL-500, CHARACTERIZATION OF VARIANT MYHRS THR-500.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

Mendelian genes SMAD family member 4 (SMAD4)

Leiden Open Variation Database (LOVD)

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF045447 , AF045438, AF045439, AF045440, AF045441, AF045442, AF045443, AF045444, AF045445, AF045446 Genomic DNA. Translation: AAC03051.1.
U44378 mRNA. Translation: AAA91041.1.
AK290770 mRNA. Translation: BAF83459.1.
CH471096 Genomic DNA. Translation: EAW62985.1.
BC002379 mRNA. Translation: AAH02379.1.

IPI

IPI00013404.

PIR

S71811.

RefSeq

NP_005350.1. NM_005359.5.

UniGene

Hs.75862.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1DD1	X-ray	2.62	A/B/C	285-552	[»]
1G88	X-ray	3.00	A/B/C	285-552	[»]
1MR1	X-ray	2.85	A/B	319-552	[»]
1U7F	X-ray	2.60	B	314-552	[»]
1U7V	X-ray	2.70	B	314-549	[»]
1YGS	X-ray	2.10	A	319-552	[»]

DisProt

DP00464.

ProteinModelPortal

Q13485.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q13485. 29 interactions.

MINT

MINT-244037.

STRING

9606.ENSP00000341551.

PTM databases

PhosphoSite

Q13485.

Polymorphism databases

DMDM

13959561.

Proteomic databases

PaxDb

Q13485.

PeptideAtlas

Q13485.

PRIDE

Q13485.

Protocols and materials databases

DNASU

4089.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000342988; ENSP00000341551; ENSG00000141646.
ENST00000398417; ENSP00000381452; ENSG00000141646.

GeneID

4089.

KEGG

hsa:4089.

UCSC

uc002lfb.4. human.

Organism-specific databases

CTD

4089.

GeneCards

GC18P048494.

HGNC

HGNC:6770. SMAD4.

HPA

CAB002312.
HPA019154.

MIM

114500. phenotype.
139210. phenotype.
174900. phenotype.
175050. phenotype.
178600. phenotype.
260350. phenotype.
600993. gene.

neXtProt

NX_Q13485.

Orphanet

1333. Familial pancreatic carcinoma.
2929. Juvenile gastrointestinal polyposis.
2588. Myhre syndrome.
774. Rendu-Osler-Weber disease.

PharmGKB

PA30527.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG286923.

HOGENOM

HOG000286019.

HOVERGEN

HBG053353.

InParanoid

Q13485.

KO

K04501.

OMA

AQPATYH.

OrthoDB

EOG4KPT9S.

PhylomeDB

Q13485.

Enzyme and pathway databases

Pathway_Interaction_DB

bmppathway. BMP receptor signaling.
wnt_canonical_pathway. Canonical Wnt signaling pathway.
hif1_tfpathway. HIF-1-alpha transcription factor network.
smad2_3pathway. Regulation of cytoplasmic and nuclear SMAD2/3 signaling.
smad2_3nuclearpathway. Regulation of nuclear SMAD2/3 signaling.
tgfbrpathway. TGF-beta receptor signaling.

Reactome

REACT_111045. Developmental Biology.
REACT_111102. Signal Transduction.
REACT_71. Gene Expression.

SignaLink

Q13485.

Gene expression databases

ArrayExpress

Q13485.

Bgee

Q13485.

CleanEx

HS_SMAD4.

Genevestigator

Q13485.

GermOnline

ENSG00000141646. Homo sapiens.

Family and domain databases

Gene3D

2.60.200.10. 1 hit.
3.90.520.10. 1 hit.

InterPro

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]

PANTHER

PTHR13703. PTHR13703. 1 hit.

Pfam

PF03165. MH1. 1 hit.
PF03166. MH2. 1 hit.
[Graphical view]

SMART

SM00523. DWA. 1 hit.
SM00524. DWB. 1 hit.
[Graphical view]

SUPFAM

SSF56366. MAD_MH1. 1 hit.
SSF49879. SMAD_FHA. 1 hit.

PROSITE

PS51075. MH1. 1 hit.
PS51076. MH2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

SMAD4. human.

EvolutionaryTrace

Q13485.

GenomeRNAi

4089.

NextBio

16030.

SOURCE

Search...

Entry information

Entry name

SMAD4_HUMAN

Accession

Primary (citable) accession number: Q13485
Secondary accession number(s): A8K405

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 4, 2001
Last sequence update:	November 1, 1996
Last modified:	May 29, 2013
This is version 154 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.