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TGF-β control of cell proliferation

Journal of Cellular Biochemistry, ISSN: 0730-2312, Vol: 96, Issue: 3, Page: 447-462
2005
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Review Description

This article focuses on recent findings that the type V TGF-β receptor (TβR-V), which co-expresses with other TGF-β receptors (TβR-I, TβR-II, and TβR-III) in all normal cell types studied, is involved in growth inhibition by IGFBP-3 and TGF-β and that TGF-β activity is regulated by two distinct endocytic pathways (clathrin-and caveolar/lipid-raft- mediated). TGF-β is a potent growth inhibitor for most cell types, including epithelial and endothelial cells. The signaling by which TGF-β controls cell proliferation is not well understood. Many lines of evidence indicate that other signaling pathways, in addition to the prominent TβR-I/TβR-II/Smad2/3/4 signaling cascade, are required for mediating TGF-β-induced growth inhibition. Recent studies revealed that TβR-V, which is identical to LRP-1, mediates IGF-independent growth inhibition by IGFBP-3 and mediates TGF-β-induced growth inhibition in concert with TβR-I and TβR-II. In addition, IRS proteins and. a Ser/Thr-specific protein phosphatase(s) are involved in the TβR-V-mediated growth inhibitory signaling cascade. The TβR-V signaling cascade appears to cross-talk with the TβR-I/TβR-II, insulin receptor (IR), IGF-I receptor (IGF-IR), integrin and c-Met signaling cascades. Attenuation or loss of the TβR-V signaling cascade may enable carcinoma cells to escape from TGF-β growth control and may contribute to the aggressiveness and invasiveness of these cells via promoting epithelial-to-mesenchymal transdifferentiation (EMT). Finally, the ratio of TGF-β binding to TβR-II and TβR-I is a signal controlling TGF-β partitioning between two distinct endocytosis pathways and resultant TGF-β responsiveness. These recent studies have provided new insights into the molecular mechanisms underlying TGF-β-induced cellular growth inhibition, cross-talk between the TβR-V and other signaling cascades, the signal that controls TGF-β responsiveness and the role of TβR-V in tumorigenesis. © 2005 Wiley-Liss, Inc.

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