Signal transduction and TGF-β superfamily receptors

Abstract

The TGF-beta superfamily includes a large number of related growth and differentiation factors expressed in virtually all phyla. Superfamily members bind to specific cell surface receptors that activate signal transduction mechanisms to elicit their effects. Candidate receptors fall into two primary groups, termed type I and type II receptors. Both types are serine/threonine kinases. Upon activation by the appropriate ligand, type I and type II receptors physically interact to form hetero-oligomers and subsequently activate intracellular signaling cascades, ultimately regulating gene transcription and expression. In addition, TGF-beta binds to a third receptor class, type III, a membrane-anchored proteoglycan lacking the kinase activity typical of signal transducing molecules. Type III receptors appear to regulate ligand availability to type I and type II receptors. Although a number of transduction mechanisms may be available to TGF-beta superfamily members, evidence gathered through the use of specific kinase and G-protein inhibitors and through assays measuring activation and levels of signaling intermediates suggests that at least one signaling pathway interacts with Ras and Raf proteins via a G-protein intermediate. Raf begins the cytoplasmic kinase cascade that leads to gene regulation. The myriad responses regulated by TGF-beta superfamily members makes the understanding of signal transduction mechanisms utilized by these proteins of great interest to a wide range of biological disciplines.

Effect of age and hypoxia on TGFβ1 receptor expression and signal transduction in human dermal fibroblasts: Impact on cell migration

“…Decreased expression of TGFbRI, RII and p42/44 MAP kinase activation in aged HDF under hypoxic conditions Cellular responsiveness of TGFb1 is dependent on binding of the growth factor with TGF receptor type II (TGFbRII) followed by recruitment of the receptor type I (TGFbRI) leading to activation of cytosolic signaling pathways including the p42/p44 MAP kinase and SMAD pathways (Kolodziejczyk and Hall, 1996;Heldin et al, 1997;Massague, 1998). We hypothesized that the reduced vulnerary response of aged animals to TGFb1 in our previous study (Wu et al, 1999) results in part from a reduced receptor expression and/or activation of downstream events in wound cells such as ®broblasts.…”

“…The ability of TGFb1 to modify cellular behavior depends on the binding of the growth factor to TGFb receptor type II (TGFbRII) followed by recruitment and activation of TGFb receptor type I (TGFbRI) (Kolodziejczyk and Hall, 1996;Heldin et al, 1997;Massague, 1998). This leads to phosphorylation-dependent activation of at least two separate pathways: the SMAD pathway and the p42/p44 mitogen-activated protein kinase (MAPK) pathway and subsequent alterations in cellular processes important for wound healing including mitogenesis, migration, and matrix production.…”

Clinical implications of growth factors in flexor tendon wound healing

“…The TGF-␤ family of proteins binds to 3 distinct membrane receptors termed RI, RII, and RIII. 130 Ligand binding causes these receptors to interact with each other, ultimately activating intracellular serine-threonine protein kinase activity.…”

Abnormal Mucosal Extracellular Matrix Deposition Is Associated with Increased TGF-β Receptor-expressing Mesenchymal Cells in a Mouse Model of Colitis

“…TGF-␤ activity is tightly regulated both during proteolytic generation of the biologically active cytokine (reviewed Keski-Oja et al 1995) and also at the level of the cellular response to active TGF-␤ (reviewed Kolodziejczyk and Hall 1996), through selective receptor expression, control of receptor density, and subsequent intracellular signaling. After activation via proteolytic cleavage, TGF-␤ operates via two major signaling receptors, type I and type II (RI and RII).…”