Premium
Identification of insulin receptor substrate proteins as key molecules for the TβR‐V/LRP‐1‐mediated growth inhibitory signaling cascade in epithelial and myeloid cells
Author(s) -
Shian Huang Shuan,
M. Leal Sandra,
Chen Chun-Lin,
Liu I-Hua,
San Huang Jung
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1872fje
Subject(s) - dephosphorylation , biology , transfection , growth inhibition , microbiology and biotechnology , receptor , insulin receptor , phosphorylation , cell growth , cell culture , insulin , biochemistry , endocrinology , insulin resistance , genetics , phosphatase
ABSTRACT The type V TGF‐β receptor (TβR‐V) mediates IGF‐independent growth inhibition by IGFBP‐3 and mediates growth inhibition by TGF‐β 1 in concert with the other TGF‐β receptor types. TβR‐V was recently found to be identical to LRP‐1. Here we find that insulin and (Q 3 A 4 Y 15 L 16 ) IGF‐I (an IGF‐I analog that has a low affinity for IGFBP‐3) antagonize growth inhibition by IGFBP‐3 in mink lung epithelial cells (Mv1Lu cells) stimulated by serum. In these cells, IGFBP‐3 induces serine‐specific dephosphorylation of IRS‐1 and IRS‐2. The IGFBP‐3‐induced dephosphorylation of IRS‐2 is prevented by cotreatment of cells with insulin, (Q 3 A 4 Y 15 L 16 ) IGF‐I, or TβR‐V/LRP‐1 antagonists. The magnitude of the IRS‐2 dephosphorylation induced by IGFBP‐3 positively correlates with the degree of growth inhibition by IGFBP‐3 in Mv1Lu cells and mutant cells derived from Mv1Lu cells. Stable transfection of murine 32D myeloid cells (which lack endogenous IRS proteins and are insensitive to growth inhibition by IGFBP‐3) with IRS‐1 or IRS‐2 cDNA confers sensitivity to growth inhibition by IGFBP‐3; this IRS‐mediated growth inhibition can be completely reversed by insulin in 32D cells stably expressing IRS‐2 and the insulin receptor. These results suggest that IRS‐1 and IRS‐2 are key molecules for the TβR‐V/LRP‐1‐mediated growth inhibitory signaling cascade.