Is Insulin Receptor Substrate4 (IRS4) a Platform Involved in the Activation of Several Oncogenes?

Abstract

The IRS (insulin receptor substrate) family of scaffold proteins includes insulin receptor substrate-4 (IRS4), which is expressed only in a few cell lines, including human kidney, brain, liver, and thymus and some cell lines. Its N-terminus carries a phosphotyrosine-binding (PTB) domain and a pleckstrin homology domain (PH), which distinguishes it as a member of this family. In this paper, we collected data about the molecular mechanisms that explain the relevance of IRS4 in the development of cancer and identify IRS4 differences that distinguish it from IRS1 and IRS2. Search engines and different databases, such as PubMed, UniProt, ENSEMBL and SCANSITE 4.0, were used. We used the name of the protein that it encodes "(IRS-4 or IRS4)", or the combination of these terms with the word "(cancer)" or "(human)", for searches. Terms related to specific tumor pathologies ("breast", "ovary", "colon", "lung", "lymphoma", etc.) were also used. Despite the lack of knowledge on IRS4, it has been reported that some cancers and benign tumors are characterized by high levels of IRS-4 expression. Specifically, the role of IRS-4 in different types of digestive tract neoplasms, gynecological tumors, lung cancers, melanomas, hematological tumors, and other less common types of cancers has been shown. IRS4 differs from IRS1 and IRS2 in that can activate several oncogenes that regulate the PI3K/Akt cascade, such as BRK and FER, which are characterized by tyrosine kinase-like activity without regulation via extracellular ligands. In addition, IRS4 can activate the CRKL oncogene, which is an adapter protein that regulates the MAP kinase cascade. Knowledge of the role played by IRS4 in cancers at the molecular level, specifically as a platform for oncogenes, may enable the identification and validation of new therapeutic targets.

Keywords: IRS4; MAPK pathway; PI3K/Akt pathway; cancer; translational biomarker.

Figure 1

Insulin/IGF1 receptors signaling. Role of IRSs in the insulin and IGF1 signaling pathways. PH = pleckstrin homology domain and PTB = phosphotyrosine-binding domain. ℗ = phosphotyrosine residues.

Figure 2

Alignment of the IRS family proteins. PH = pleckstrin homology domain and PTB = phosphotyrosine-binding domain. The asterisk represents tyrosine residues that can be phosphorylated in the presence of insulin. Adapted from [1].

Figure 3

Classical signaling cascades common to IRS1/2/4 involved in cell cycle control and regulation of metabolism. Adapted from [3].

Figure 4

Signaling pathways specific of IRS4. Location of IRS4-specific domains involved in the control of the PI3K/AKT (A) and MAP kinase (B) cascades. PH = pleckstrin homology domain and PTB = phosphotyrosine-binding domain. PRD = proline rich domain.

Figure 5

Different signaling pathways in which the IRS4 participates. BMP = bone morphogenetic protein. FGF2 = fibroblast growth factor 2.

Figure 6

Proposed model of IRS4-mediated oncogenic transformation. General summary on the regulation of IRS4 expression and its role in the control of non-canonical AKT pathways.