Reactome: A Curated Pathway Database

Signaling by TGF-beta Receptor Complex in Cancer (R-HSA-3304351)

Species Homo sapiens

Summation

Signaling by the TGF-beta receptor complex is tumor suppressive, as it inhibits cell growth and promotes cell differentiation and apoptosis (Shipley et al. 1986, Hannon et al. 1994, Datto et al. 1995, Chen et al. 2002, Azar et al. 2009). TGF-beta signaling is frequently impaired in cancer, mostly through SMAD4 gene deletion or loss-of-function mutations, which are especially frequent in pancreatic cancer (Hahn et al. 1996, Shi et al. 1997, Fleming et al. 2013). Signaling by TGF-beta receptor complex can also be disrupted by loss-of-function mutations in SMAD2 and SMAD3 (Fleming et al. 2013) or loss-of-function mutations in TGFBR2 (TGF-beta receptor II) (Markowitz et al. 1995, Garrigue-Antar et al. 1995, Parsons et al. 1995, Grady et al. 1999) or TGFBR1 (TGF-beta receptor I) (Chen et al. 1998, Chen et al. 2001, Goudie et al. 2011).

In advanced cancer, signaling by TGF-beta may be tumor promoting, as it induces epithelial-to-mesenchymal transition (EMT), thereby increasing invasiveness (Cui et al. 1996, Guasch et al. 2007, reviewed by Heldin et al. 2012).

Locations in the PathwayBrowser
Diseases
Name Identifier Synonyms
cancer 162 [malignant tumor, malignant neoplasm, primary cancer]
Literature References
pubMedId Title Journal Year
8553070 DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 Science 1996
23139211 SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer Cancer Res. 2013
7664267 Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma cells Cancer Res. 1995
7585632 Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer Cancer Res. 1995
9214508 A structural basis for mutational inactivation of the tumour suppressor Smad4 Nature 1997
22710176 Regulation of EMT by TGF? in cancer FEBS Lett. 2012
7761852 Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability Science 1995
9927040 Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers Cancer Res. 1999
2418960 Reversible inhibition of normal human prokeratinocyte proliferation by type beta transforming growth factor-growth inhibitor in serum-free medium Cancer Res. 1986
7777546 Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism Proc. Natl. Acad. Sci. U.S.A. 1995
8078588 p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest Nature 1994
12150994 E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression Cell 2002
19834456 4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation EMBO J. 2009
21358634 Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1 Nat. Genet. 2011
9809982 Transforming growth factor beta type I receptor kinase mutant associated with metastatic breast cancer Cancer Res. 1998
11406536 Transforming growth factor-beta receptor type I gene is frequently mutated in ovarian carcinomas Cancer Res. 2001
11477574 Novel inactivating mutations of transforming growth factor-beta type I receptor gene in head-and-neck cancer metastases Int. J. Cancer 2001
8752208 TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice Cell 1996
17936557 Loss of TGFbeta signaling destabilizes homeostasis and promotes squamous cell carcinomas in stratified epithelia Cancer Cell 2007