The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

TGF-beta signal transduction.

https://www.cell.com/cell/pdf/S0092-8674(03)00432-X.pdf

Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus

The recent identification of the SMAD family of signal transducer proteins has unravelled the mechanisms by which transforming growth factor-beta (TGF-beta) signals from the cell membrane to the nucleus. Pathway-restricted SMADs are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-beta. Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADs.

TGF-beta signalling from cell membrane to nucleus through SMAD proteins

Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.

/pdf/consensus-coding-sequences-of-human-breast-and-colorectal-15edxp2i8x.pdf

Consensus coding sequences of human breast and colorectal cancers

Tgfbeta signaling in growth control, cancer, and heritable disorders

https://www.cell.com/cell/pdf/S0092-8674(00)80128-2.pdf

Rosa Pirone

Papers

MADR2 maps to 18q21 and encodes a TGFβ-regulated MAD-related protein that is functionally mutated in colorectal carcinoma

MADR2 Is a Substrate of the TGFβ Receptor and Its Phosphorylation Is Required for Nuclear Accumulation and Signaling

Urinary thiosulfate determined by suppressed ion chromatography with conductimetric detection