A partial amino acid sequence of human platelet-derived growth factor, the major mitogen in serum for cells of mesenchymal origin, has been determined. A region of 104 contiguous amino acids shows virtual identity with the predicted sequence of p28sis, the putative transforming protein of simian sarcoma virus (SSV). This similarity suggests a mechanism for transformation by SSV and other agents, involving expression of growth factors.

Insulin-like growth factor-binding protein 3 (IGFBP-3) has been shown to inhibit cell growth by IGF-dependent and -independent mechanisms. The putative cell-surface IGFBP-3 receptor that mediates the IGF-independent growth inhibition has not been identified. Here we show that recombinant human IGFBP-3 inhibits 125 Itransforming growth factor (TGF)-␤ 1 binding to the type V TGF-␤ receptor (M r 400,000) in mink lung epithelial cells. We also demonstrate that the ϳ400-kDa

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

The type V TGF-beta receptor (TbetaR-V)/IGFBP-3 receptor mediates the IGF-independent growth inhibition induced by IGFBP-3. It also mediates the growth inhibitory response to TGF-beta1 in concert with other TGF-beta receptor types, and its loss may contribute to the malignant phenotype of human carcinoma cells. Here we demonstrate that TbetaR-V is identical to LRP-1/alpha2M receptor as shown by MALDI-TOF analysis of tryptic peptides of TbetaR-V purified from bovine liver. In addition, 125I-IGFBP-3 affinity-labeled TbetaR-V in Mv1Lu cells is immunoprecipitated by antibodies to LRP-1 and TbetaR-V. RAP, an LRP-1 antagonist, inhibits binding of 125I-TGF-beta1 and 125I-IGFBP-3 to TbetaR-V and diminishes IGFBP-3-induced growth inhibition in Mv1Lu cells. Absent or low levels of LRP-1, as with TbetaR-V, have been linked to the malignant phenotype of carcinoma cells. Mutagenized Mv1Lu cells selected for reduced expression of LRP-1 have an attenuated growth inhibitory response to TGF-beta1 and IGFBP-3. LRP-1-deficient mouse embryonic fibroblasts lack a growth inhibitory response to TGF-beta1 and IGFBP-3. On the other hand, stable transfection of H1299 human lung carcinoma cells with LRP-1 cDNA restores the growth inhibitory response. These results suggest that the LRP-1/TbetaR-V/IGFBP-3 receptor is required for the growth inhibitory response to IGFBP-3 and TGF-beta1.

The platelet-derived growth factor (PDGF) is shown to be chemotactic for monocytes and neutrophils. Maximum monocyte chemotaxis to PDGF is fully equal to that achieved with C5a and occurs at congruent to 20 ng/ml (congruent to 0.7 nM). Maximum neutrophil chemotaxis is congruent to 60% that achieved with C5A but occurs at congruent to 1 ng/ml (congruent to 32 pM). The chemotactic activity of PDGF is blocked by specific antisera to PDGF and by protamine sulfate, a competitive inhibitor of PDGF binding to cell surfaces. In contrast to PDGF, epidermal growth factor shows no chemotactic activity for inflammatory cells at 0.5-100 ng/ml. The high level of chemotactic activity of PDGF suggests that in addition to its role as a mitogen for smooth muscle cells and fibroblasts, PDGF may be involved in attracting inflammatory cells to sites of platelet release.