TGF-β control of cell proliferation

This article focuses on recent findings that the type V TGF-beta receptor (T beta R-V), which co-expresses with other TGF-beta receptors (T beta R-I, T beta R-II, and T beta R-III) in all normal cell types studied, is involved in growth inhibition by IGFBP-3 and TGF-beta and that TGF-beta activity is regulated by two distinct endocytic pathways (clathrin- and caveolar/lipid-raft-mediated). TGF-beta is a potent growth inhibitor for most cell types, including epithelial and endothelial cells. The signaling by which TGF-beta controls cell proliferation is not well understood. Many lines of evidence indicate that other signaling pathways, in addition to the prominent T beta R-I/T beta R-II/Smad2/3/4 signaling cascade, are required for mediating TGF-beta-induced growth inhibition. Recent studies revealed that T beta R-V, which is identical to LRP-1, mediates IGF-independent growth inhibition by IGFBP-3 and mediates TGF-beta-induced growth inhibition in concert with T beta R-I and T beta R-II. In addition, IRS proteins and a Ser/Thr-specific protein phosphatase(s) are involved in the T beta R-V-mediated growth inhibitory signaling cascade. The T beta R-V signaling cascade appears to cross-talk with the T beta R-I/T beta R-II, insulin receptor (IR), IGF-I receptor (IGF-IR), integrin and c-Met signaling cascades. Attenuation or loss of the T R-V signaling cascade may enable carcinoma cells to escape from TGF-beta growth control and may contribute to the aggressiveness and invasiveness of these cells via promoting epithelial-to-mesenchymal trans differentiation (EMT). Finally, the ratio of TGF-beta binding to T beta R-II and T beta R-I is a signal controlling TGF-beta partitioning between two distinct endocytosis pathways and resultant TGF-beta responsiveness. These recent studies have provided new insights into the molecular mechanisms underlying TGF-beta-induced cellular growth inhibition, cross-talk between the T beta R-V and other signaling cascades, the signal that controls TGF-beta responsiveness and the role of T beta R-V in tumorigenesis.