Premium
The insulin receptor translocates to the nucleus to regulate cell proliferation in liver
Author(s) -
Amaya Maria J.,
Oliveira André G.,
Guimarães Erika S.,
Casteluber Marisa C.F.,
Carvalho Sandhra M.,
Andrade Lidia M.,
Pinto Mauro C.X.,
Men Albert,
Oliveira Cleida A.,
Resende Rodrigo R.,
Menezes Gustavo B.,
Nathanson Michael H.,
Leite M. Fatima
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26609
Subject(s) - insulin receptor , nucleus , insulin , microbiology and biotechnology , biology , signal transduction , cell nucleus , medicine , liver cell , cell growth , endocrinology , cytosol , insulin resistance , biochemistry , enzyme
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 Ca 2+ signals within the nucleus regulate cell proliferation, we investigated whether insulin's mitogenic effects result from activation of Ca 2+ ‐signaling pathways by IRs within the nucleus. Insulin‐induced increases in Ca 2+ 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 (InsP 3 ) 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 the formation of InsP 3 in the nucleus, but not the cytosol, whereas hepatic glucose metabolism was not affected by buffering InsP 3 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 InsP 3 ‐dependent Ca 2+ ‐signaling pathways. The steps along this signaling pathway reveal a number of potential targets for therapeutic modulation of liver growth in health and disease. (H epatology 2014;58:274–283)