Nuclear IRS‐1 and cancer

Abstract

The family of insulin receptor substrates (IRS) consists of four proteins (IRS-1 - IRS-4), which were initially characterized as typical cytosolic adaptor proteins involved in insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) signaling. The first cloned and characterized member of the IRS family, IRS-1, has predicted molecular weight of 132 kDa, however, as a result of its extensive serine phosphorylation it separates on a SDS gel as a band of approximately 160–185 kDa. In addition to its metabolic and growth-promoting functions, IRS-1 is also suspected to play a role in malignant transformation. The mechanism by which IRS-1 supports tumor growth is not fully understood, and the argument that IRS-1 merely amplifies the signal from the IGF-1R and/or IR requires further investigation. Almost a decade ago, we reported the presence of nuclear IRS-1 in medulloblastoma clinical samples, which express viral oncoprotein, large T-antigen of human polyomavirus JC (JCV T-antigen). This first demonstration of nuclear IRS-1 was confirmed in several other laboratories. The nuclear IRS-1 was also detected by cells expressing the SV40 T-antigen, v-Src, in immortalized fibroblasts stimulated with IGF-I, in hepatocytes, 32D cells, and in an osteosarcoma cell line. More recently, nuclear IRS-1 was detected in breast cancer cells in association with estrogen receptor alpha (ERα), and in JC virus negative medulloblastoma cells expressing ERβ, further implicating nuclear IRS-1 in cellular transformation. Here, we discuss how nuclear IRS-1 acting on DNA repair fidelity, transcriptional activity, and cell growth can support tumor development and progression.

Amyloid β oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes

“…In addition, the present study showed that phosphorylated IRS-1 was mainly distributed in the nucleus of astrocytes treated with Aβ 1-42 oligomers, which was consistent with previous results found in neurons treated with Aβ 1-42 oligomers (Ma et al, 2009). Several studies show that nuclear IRS-1 regulates the activity of the rDNA, cyclin D1 and c-myc promoters, which may contribute to cell proliferation and cell cycle progression in PI3K independent pathway (Tu et al, 2002;Chen et al, 2005;Wu et al, 2008;Reiss et al, 2012). In addition, a recent study shows that IRS-1 is associated with small nuclear RNA that contributes to ribosome biogenesis (Ozoe et al, 2014).…”

Altered gene expression patterns during the initiation and promotion stages of neonatally diethylstilbestrol-induced hyperplasia/dysplasia/neoplasia in the hamster uterus

“…The family of insulin receptor substrate proteins (IRS-1 – IRS-4) serve as intermediates in the action of cell surface receptors that, in addition to their metabolic and growth regulation functions, are implicated in malignant transformation [31, 32]. We found that the IRS-1 family member protein was down-regulated (67%).…”

“…However, discrepancies from this view, including evidence of nuclear IRS-1 localization/action [32] and its down-regulation in some tumors [75] do exist. Our IRS-1 expression observations do not easily align with such disparate reports.…”

Alpha-synuclein overexpression negatively regulates insulin receptor substrate 1 by activating mTORC1/S6K1 signaling

“…There are six members of the IRS family, of which IRS-1 is the best characterized (Reiss et al, 2012). Recent reports suggest that IRS-2 serine phosphorylation is increased and total IRS-2 level is decreased in a 6-hydroxydopamine (OHDA) PD animal model (Morris et al, 2008), while other studies have shown that total IRS-1 was decreased in a 6-OHDA cell model of PD (Kim et al, 2014).…”