Mechanism of transforming growth factor-β1 signaling: Role of the mitogen-activated protein kinase

Transforming growth factor-beta 1 (TGF-beta 1) regulates diverse biologic activities including cell growth, cell death or apoptosis, cell differentiation, 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 nephropathy. TGF-beta 1 actions are mediated by the heteromeric interactions of 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 transphosphorylates TGF-beta type I receptor (T beta R-I). However, the signaling pathway following the initial receptor interaction with ligand remains poorly understood. Much of current investigation, including in our laboratory, is now focused on the elucidation of the intracellular signaling components that mediate TGF-beta 1 signals downstream of the cell-surface receptors. An emerging body of evidence implicates the mitogen-activated protein kinase (MAPK) as an important TGF-beta 1 signaling pathway.