Loss of Function of SMAD2/3 in Cancer

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R-HSA-3304349
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Homo sapiens
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Loss-of-function of SMAD2 and SMAD3 in cancer occurs less frequently than the loss of SMAD4 function and was studied in most detail in colorectal cancer (Fleming et al. 2013).


Similarly to SMAD4, coding sequence mutations in SMAD2 and SMAD3 in cancer cluster in the MH2 domain, involved in the formation of transcriptionally active heterotrimers with SMAD4. Another region of SMAD2 and SMAD3 that is frequently mutated in cancer is the phosphorylation motif Ser-Ser-X-Ser at the very C-terminus (Fleming et al. 2013). The phosphorylation of this conserved motif by the activated TGF-beta receptor complex is an essential step in SMAD2 and SMAD3 activation and a prerequisite for the formation of heterotrimers with SMAD4 (Chacko et al. 2001, Chacko et al. 2004).

Smad2 knockout mice die at embryonic day 8.5, with impaired visceral endoderm function and deficiency in mesoderm formation. Smad2+/- heterozygotes appear normal and are fertile (Hamamoto et al. 2002). While polyps of compound Smad2+/-;Apc+/- mice show no difference in the number, size or histopathology from the polyps of Apc+/- mice (Takaku et al. 2002, Hamamoto et al. 2002), Smad2+/-;Apc+/- mice develop extremely large intestinal tumors and multiple invasive cancers not observed in Apc+/- mice. Therefore, loss of Smad2 does not contribute to initiation of intestinal tumorigenesis, but accelerates malignant progression (Hamamoto et al. 2002). Smad3 knockout mice are viable and fertile but die between 4 and 6 months of age from colorectal adenocarcinoma (Zhu et al. 1998), indicating that the loss of Smad3 initiates intestinal tumorigenesis.

Literature References
PubMed ID Title Journal Year
15350224 Structural basis of heteromeric smad protein assembly in TGF-beta signaling

Chacko, BM, Qin, BY, Tiwari, A, Shi, G, Lam, S, Hayward, LJ, De Caestecker, M, Lin, K

Mol Cell 2004
12384562 Compound disruption of smad2 accelerates malignant progression of intestinal tumors in apc knockout mice

Hamamoto, T, Beppu, H, Okada, H, Kawabata, M, Kitamura, T, Miyazono, K, Kato, M

Cancer Res. 2002
9753318 Smad3 mutant mice develop metastatic colorectal cancer

Zhu, Y, Richardson, JA, Parada, LF, Graff, JM

Cell 1998
11224571 The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization

Chacko, BM, Qin, B, Correia, JJ, Lam, SS, de Caestecker, MP, Lin, K

Nat. Struct. Biol. 2001
23139211 SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer

Fleming, NI, Jorissen, RN, Mouradov, D, Christie, M, Sakthianandeswaren, A, Palmieri, M, Day, F, Li, S, Tsui, C, Lipton, L, Desai, J, Jones, IT, McLaughlin, S, Ward, RL, Hawkins, NJ, Ruszkiewicz, AR, Moore, J, Zhu, HJ, Mariadason, JM, Burgess, AW, Busam, D, Zhao, Q, Strausberg, RL, Gibbs, P, Sieber, OM

Cancer Res. 2013
12183405 No effects of Smad2 (madh2) null mutation on malignant progression of intestinal polyps in Apc(delta716) knockout mice

Takaku, K, Wrana, JL, Robertson, EJ, Taketo, MM

Cancer Res. 2002
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Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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