Integration of the TGF-beta pathway into the cellular signalling network.

Transforming growth factor-betas (TGF-betas) regulate pivotal cellular processes such as proliferation, differentiation and apoptosis. After ligand binding, the signals are transmitted by two types of transmembrane serine/threonine kinase receptors. The type I receptor phosphorylates Smad proteins, intracellular effectors which upon oligomerization enter the nucleus to regulate transcription following assembly with transcriptional co-factors and co-modulators. The cellular distribution of TGF-beta receptors along with their oligomerization mode and their complex formation with different cell surface receptors represent crucial steps in determining the initiation of distinct signalling cascades. In addition, the broad array of intracellular proteins that influence the TGF-beta pathway demonstrates that signal transduction does not proceed in a linear fashion but rather comprises a complex network of cascades that mutually influence each other. The present review describes the intricate control of TGF-beta signal transduction on various levels of the cascade with particular focus (i) on the assembly of different receptor subtypes and (ii) on the multitude of crosstalk with signal transducers from other pathways. Integration of the TGF-beta/Smad pathway into the signalling network has taken on added importance as it substantially contributes to elicit the plethora of cell- and tissue-specific effects of TGF-beta.