Transforming growth factor-beta signal transduction and progressive renal disease

Transforming growth factor-beta (TGF-beta) superfamily members are multifunctional growth factors that play pivotal roles in development and tissue homeostasis. Recent studies have underscored the importance of TGF-beta in regulation of cell proliferation and extracellular matrix synthesis and deposition. TGF-beta signaling is initiated by ligand binding to a membrane-associated receptor complex that has serine/threonine kinase activity. This receptor complex phosphorylates specific Smad proteins, which then transduce the ligand-activated signal to the nucleus. Smad complexes regulate target gene transcription either by directly binding DNA sequences, or by complexing with other transcription factors or co-activators. There is extensive crosstalk between the TGF-beta signaling pathway and other signaling systems, including the mitogen-activated protein kinase pathways. The importance of TGF-beta in regulation of cell growth has been emphasized by recent observations that mutations of critical elements of the TGF-beta signaling system are associated with tumor progression in patients with many different types of epithelial neoplasms. TGF-beta has emerged as a predominant mediator of extracellular matrix production and deposition in progressive renal disease and in other forms of chronic tissue injury. In this overview, recent advances in our understanding of TGF-beta signaling, cell cycle regulation by TGF-beta, and the role of TGF-beta in progressive renal injury are highlighted.