Role of IRS-4 in PI3-K activation by insulin in HEPG2 cells, modulation by Angiotensin II

VILLARREAL, RODRIGO SEBASTIÁN; FORNERIS, MYRIAM LILIANA; URANGA, ROMINA MARÍA; SALVADOR, GABRIELA ALEJANDRA; CIUFFO, GLADYS MARÍA

REGULATORY PEPTIDES

Elsevier/North Holland

Lugar: Amsterdam; Año: 2010 vol. 161 p. 67 - 72

0167-0115

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US;} @page Section1 {size:595.3pt 841.9pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Insulin receptor substrate–4 (IRS-4) has a limited tissue expression and its modulation by tyr-phosphorylation is still controversial. We evaluated the participation of IRS-4 in the cross-talk between Angiotensin II (Ang II) and Insulin (Ins) receptors in HepG2 cells. Ins (10-7 M) induced tyr-phosphorylation of IRS-4 (maximal at 5 min), an effect potentiated by Ang II AT1 receptors. Phosphatydilinositol-3 kinase (PI3-K) inhibitors Wortmanin or LY294002 reduced Ang II effect on tyr-phosphorylation of IRS-4 to a level comparable to that of Ins alone. Physical association between IRS-4 substrate and PI3-K was demonstrated by coimmunoprecipitation. Recruitment of PI3-K by IRS-4 was induced by Ins (10-7 M, 5 min) not by Ang II (10-7 M) and this was inhibited by Wortmanin and LY294002. Ang II did not modify either the association or activation of PI3-K in immunocomplexes. The present data provide novel evidence of IRS-4 phosphorylation mediated by Ins, an effect modulated by Ang II. We report also Ins-induced PI3-K activation mediated by IRS-4. Our findings suggest a role for IRS-4 as a docking protein in the Ins signaling pathway that involves PI3-K association and activation. The present data suggest a possible participation of IRS-4 in cell proliferation Ins-induced.