Mechanism of transforming growth factor-beta 1 signaling: Role of the mitogen-activated protein kinase

Transforming growth factor-beta 1 (TGF-beta 1) regulates diverse biologic a ctivities including cell growth, cell death or apoptosis, cell differentiat ion, and extracellular matrix (ECM) synthesis. TGF-beta 1 is believed to be a key mediator of tissue fibrosis as a consequence of ECM accumulation in pathologic states such as progressive renal diseases including diabetic nep hropathy. TGF-beta 1 actions are mediated by the heteromeric interactions o f types I and II serine/threonine kinase receptors. Initiation of signaling requires binding of TGF-beta 1 to TGF-beta type TT receptor (T beta R-II), a constitutively active serine/threonine kinase, which subsequently transp hosphorylates TGF-beta type I receptor (T beta R-I). However, the signaling pathway following the initial receptor interaction with ligand remains poo rly understood. Much of current investigation, including in our laboratory, is now focused on the elucidation of the intracellular signaling component s that mediate TGF-beta 1 signals downstream of the cell-surface receptors. An emerging body of evidence implicates the mitogen-activated protein kina se (MAPK) as an important TGF-beta 1 signaling pathway.