rigenic one by mechanisms that are poorly understood. In the normal pathway binding of Tgf to receptor type II leads to activation of receptor type I, recruitment and phosphorylation of Smad proteins that subsequently translocate to the nucleus. Selective interactions with co-factors regulate the expression of distinct sets of target genes. Scaffolds, co-receptor, inhibitory Smad(s), ligand binding proteins provide various layers of regulation. [To access the diagram page for the normal Tgf-beta signaling pathway click here]. Genes whose mutations have been associated with colorectal cancer (CRC) include both type I and II Tgf-b receptors. Insertions/deletions mutations within a polyadenine tract in the coding sequence of receptor type II have been found in more than 50% of CRC cases associated with defects in DNA mismatch repair pathway, a well known cause of the hereditary form and a fraction of the sporadic form of the disease. Defective Smads have also been identified. Smad4 - originally cloned as deleted in pancreatic cancer 4 - is mutated or deleted in ~20% of cases; Smad2 mutations have been detected in a smaller fraction of cases; Smad3 was not thought to be involved in the disease but a missense mutation in a CRC cell line has been found. Elevated levels of Tgf1 or Smad7 have been found in patients with the disease and Smad7 polymorphism has been reported. Altered Tgf-beta signaling has also been implicated in other types of cancer such as pancreatic, prostate and gastric among others. Alterations in the core components of the pathway lead to defective or non-functional genes affecting or even abrogating the outcomes of Tgf-beta Smad dependent signaling. Altered genes are color coded. To see the ontology report for annotations, GViewer and download click here...(less)