Dimeric TGFB1 does not bind TGFBR2 MSI frameshift mutants

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R-HSA-3642203
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Reaction [transition]
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Homo sapiens
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Inactivating mutations in TGF-beta receptor II (TGFBR2) are found in the majority of colorectal cancers with microsatellite instability (MSI). MSI is frequently observed in hereditary nonpolyposis colorectal cancers (HNPCC) caused by defects in mismatch repair genes, which leads to elevated gene mutation rates, especially within simple repeated sequences (Aaltonen et al. 1994, Fishel et al. 1993, Leach et al. 1993, Nicolaides et al. 1994, Bronner et al. 1994, Miyaki et al. 1997, Wu et al. 2001). As TGFBR2 cDNA contains a repeat sequence of 10 adenines at coding nucleotides 374-383 (nucleotides 756-765 of the reference TGFBR2 mRNA NM_003242.5), it is susceptible to the MSI-associated mutator mechanism. The majority of TGFBR2 mutations observed in MSI colorectal cancer tumors are deletions of 1 or 2 adenines within the 10 adenine repeat sequence, resulting in a frameshift that is prediced to produce truncated proteins of 161 (TGFBR2 K128fs*35) and 129 amino acids (TGFBR2 K128fs*3), respectively. As these frameshift mutations produce a nonsense codon in the 5' half of the mRNA, the majority of mutant transcripts are degraded, likely through nonsense-mediated decay (Hagan et al. 1995), resulting in very low levels of mutant TGFBR2 mRNAs (Markowitz et al. 1995, Wang et al. 1995). Even if the mutant mRNA gets translated, the mutant proteins cannot be expressed at the cell surface, as the truncation is located upstream of the transmembrane domain of TGFBR2.

Cancer cells with MSI frameshift mutations in the TGFBR2 gene do not express any TGFBR2 on their cell surface and are resistant to TGF-beta 1 (TGFB1)-mediated growth inhibition (Markowitz et al. 1995, Wang et al. 1995). The responsiveness to TGFB1 can be restored by exogenous expression of the wild-type TGFBR2 (Wang et al. 1995), as long as the downstream effectors of TGF-beta receptor complex signaling are intact.

Literature References
PubMed ID Title Journal Year
11586295 A role for MLH3 in hereditary nonpolyposis colorectal cancer

Wu, Y, Berends, MJ, Sijmons, RH, Mensink, RG, Verlind, E, Kooi, KA, van der Sluis, T, Kempinga, C, van dDer Zee, AG, Hollema, H, Buys, CH, Kleibeuker, JH, Hofstra, RM

Nat. Genet. 2001
7823948 Characterization of cis-acting sequences and decay intermediates involved in nonsense-mediated mRNA turnover

Hagan, KW, Ruiz-Echevarria, MJ, Quan, Y, Peltz, SW

Mol. Cell. Biol. 1995
7761852 Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability

Markowitz, S, Wang, J, Myeroff, L, Parsons, R, Sun, L, Lutterbaugh, J, Fan, RS, Zborowska, E, Kinzler, KW, Vogelstein, B

Science 1995
8252616 The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer

Fishel, R, Lescoe, MK, Rao, MR, Copeland, NG, Jenkins, NA, Garber, J, Kane, M, Kolodner, R

Cell 1993
7665626 Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells

Wang, J, Sun, L, Myeroff, L, Wang, X, Gentry, LE, Yang, J, Liang, J, Zborowska, E, Markowitz, S, Willson, JK

J. Biol. Chem. 1995
8261515 Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer

Leach, FS, Nicolaides, NC, Papadopoulos, N, Liu, B, Jen, J, Parsons, R, Peltomäki, P, Sistonen, P, Aaltonen, LA, Nyström-Lahti, M

Cell 1993
8145827 Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer

Bronner, CE, Baker, SM, Morrison, PT, Warren, G, Smith, LG, Lescoe, MK, Kane, M, Earabino, C, Lipford, J, Lindblom, A

Nature 1994
8072530 Mutations of two PMS homologues in hereditary nonpolyposis colon cancer

Nicolaides, NC, Papadopoulos, N, Liu, B, Wei, YF, Carter, KC, Ruben, SM, Rosen, CA, Haseltine, WA, Fleischmann, RD, Fraser, CM

Nature 1994
8484121 Clues to the pathogenesis of familial colorectal cancer

Aaltonen, LA, Peltomäki, P, Leach, FS, Sistonen, P, Pylkkänen, L, Mecklin, JP, Järvinen, H, Powell, SM, Jen, J, Hamilton, SR

Science 1993
9354786 Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer

Miyaki, M, Konishi, M, Tanaka, K, Kikuchi-Yanoshita, R, Muraoka, M, Yasuno, M, Igari, T, Koike, M, Chiba, M, Mori, T

Nat. Genet. 1997
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cancer 162 malignant tumor, malignant neoplasm, primary cancer
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