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Review
. 2012 Aug;227(8):2992-3000.
doi: 10.1002/jcp.24019.

Nuclear IRS-1 and cancer

Krzysztof Reiss  1 , Luis Del Valle, Adam Lassak, Joanna Trojanek
Affiliations
Review

Nuclear IRS-1 and cancer

Krzysztof Reiss et al. J Cell Physiol. 2012 Aug.

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 a 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 by several other laboratories. 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 estrogen receptor beta (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.

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Figures

Figure 1
Figure 1. Schematic diagram of mouse IRS-1 protein
There are two major functional domains within the N-terminus portion of IRS-1: pleckstrin homology domain (PH), spanning between amino acids 0–155, and phosphotyrozine binding domain (PTB) located between amino acids 155–302. Black arrows indicate exact binding sites for PI3 kinase, Grab2 and SHP2 at indicated tyrosine residues (Y). Functionally relevant serine residues (S) and their corresponding amino acid positions are also indicated. Blue arrows indicate putative binding regions for proteins, which are suspected to translocate IRS-1 to the nucleus, including nucleolin, polyomavirus T-antigens (JCV and SV40), estrogen receptor α (ERα) and estrogen receptor β (ERβ). Other indicated sites include the binding between IRS-1 and DNA repair protein, Rad51, and positions of putative nuclear localization signals (NLS).
Figure 2
Figure 2. The IGF-IR-IRS-1-JCV T-antigen signaling interplay: effects on cell proliferation cell survival and DNA repair fidelity
Here we propose a sequence of events in which ligand activated IGF-IR triggers multiple signaling responses leading to synchronized activation of cell proliferation (SHC or IRS-1-mediated activation of Ras-MAP kinase pathways); protection from apoptosis (IRS-1 induced activation of Akt); and DNA repair by homologous recombination. The IGF-I-mediated phosphorylation of IRS-1 seems to play a critical role in this model. In the absence of IGF-I a fraction of hypo-phosphorylated IRS-1 accumulates in the perinuclear region in complex with Rad51 (Trojanek et al., 2003). Following IGF-I stimulation, activated IGF-IR phosphorylates IRS-1 on multiple tyrosine residues, decreasing the affinity of IRS-1 to Rad51, and engages IRS-1 in multiple signaling events supporting IGF-I-induced cell proliferation and cell survival (Reiss et al., 1998; Trojanek et al., 2006b; Trojanek et al., 2003). If at the same time DNA double strands (DSBs) are formed (either naturally or by genotoxic treatment), the cell can repair them in a faithful manner, by Rad51-supported homologous recombination directed DNA repair (HRR), or less faithfully, by non-homologous end joining (NHEJ). In the presence of JCV T-antigen cells can proliferation because of p53, pRb inactivation. In parallel, JCV T-antigen translocates IRS-1 to the nucleus (Lassak et al., 2002), thus creating a condition in which IRS-1 can bind Rad51 in the subcellular compartment in which Rad51 is expected to support HRR. Therefore, if JCV T-antigen expressing cells experience extensive DNA damage, the resulting DNA double strand breaks (DSBs) can either trigger apoptosis, or if NHEJ will compensate for the impaired HRR, spontaneous mutations can accumulate in the surviving cells. These mutations when accumulate may provide the cells with growth and survival advantage, which could result in the selection of clone/s initiating tumor development and progression.
Figure 3
Figure 3. Nuclear translocation of IRS-1 in Medulloblastomas
Immunohistochemistry for the IGF-IR/IR docking molecule, IRS-1, shows a prominent nuclear localization in clinical samples of medulloblastomas that express the JCV early oncoprotein, large T-antigen (upper panels). In T-antigen negative samples, IRS-1 remains in the cytoplasm of neoplastic cells (middle panels). In some tumors that lack T-antigen expression IRS-1 is still located to the nucleus in association with Estrogen Receptor beta (lower panels). Original magnification for all panels 600x.
Figure 4
Figure 4. Nuclear translocation of IRS-1 in Glioblastomas
In a similar patter of expression, IRS-1 is detected by immunohistochemistry in the cytoplasm and nuclei of neoplastic cells in cases of Glioblastoma multiforme that are positive for JCV T-Antigen (upper panels). However, tumors that lack T-antigen demonstrate exclusive cytoplasmic IRS-1 (middle panels). Finally, IRS-1 can be translocated to the nucleus in the presence of Estrogen Receptor beta (lower panels). All panels original magnification 600x.
Figure 5
Figure 5
Schematic illustration summarizing mechanisms involved in IRS-1 nuclear translocation and basic cellular processes affected by nuclear IRS-1.
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