Article
The insulin receptor translocates to the nucleus to regulate cell proliferation in liver
Registro en:
GUTIÉRREZ, Maria Jimena Amaya et al. The Insulin Receptor Translocates to the Nucleus to Regulate Cell Proliferation in Liver. Hepatology, v. 59, n. 1, p. 274-283, 2014.
0270-9139
10.1002/hep.26609
Autor
Gutiérrez, Maria Jimena Amaya
Oliveira, André Gustavo
Guimarães, Erika Sousa
Casteluber, Marisa Cristina Fonseca
Carvalho, Sandhra Maria de
Andrade, Lídia Maria de
Pinto, Mauro Cunha Xavier
Mennone, Albert
Oliveira, Cleida Aparecida de
Resende, Rodrigo Ribeiro
Menezes, Gustavo Batista de
Nathanson, Michael Harris
Leite, Maria de Fátima
Resumen
Insulin’s metabolic effects in the liver are widely appreciated, but insulin’s ability to act as a hepatic mitogen is less well understood. Because the Insulin Receptor (IR) can traffic to the nucleus, and calcium (Ca2+) signals within the nucleus regulate cell proliferation, we investigated whether insulin’s mitogenic effects result from activation of Ca2+ signaling pathways by IRs within the nucleus. Insulin-induced increases in Ca2+ and cell proliferation depended upon clathrin- and caveolin-dependent translocation of the IR to the nucleus, as well as upon formation of inositol 1,4,5,-trisphosphate (InsP3) in the nucleus, whereas insulin’s metabolic effects did not depend on either of these events. Moreover, liver regeneration after partial hepatectomy also depended upon formation of InsP3 in the nucleus but not the cytosol, whereas hepatic glucose metabolism was not affected by buffering InsP3 in the nucleus. Conclusion: These findings provide evidence that insulin’s mitogenic effects are mediated by a subpopulation of IRs that traffic to the nucleus to locally activate InsP3-dependent Ca2+ signaling pathways. The steps along this signaling pathway reveal a number of potential targets for therapeutic modulation of liver growth in health and disease.