Identification of a Novel Invasion-Promoting Region in Insulin Receptor Substrate 2

Abstract

Although the insulin receptor substrate (IRS) proteins IRS1 and IRS2 share considerable homology and activate common signaling pathways, their contributions to breast cancer are distinct. IRS1 has been implicated in the proliferation and survival of breast tumor cells. In contrast, IRS2 facilitates glycolysis, invasion, and metastasis. To determine the mechanistic basis for IRS2-dependent functions, we investigated unique structural features of IRS2 that are required for invasion. Our studies revealed that the ability of IRS2 to promote invasion is dependent upon upstream insulin-like growth factor 1 receptor (IGF-1R)/insulin receptor (IR) activation and the recruitment and activation of phosphatidylinositol 3-kinase (PI3K), functions shared with IRS1. In addition, a 174-amino-acid region in the IRS2 C-terminal tail, which is not conserved in IRS1, is also required for IRS2-mediated invasion. Importantly, this "invasion (INV) region" is sufficient to confer invasion-promoting ability when swapped into IRS1. However, the INV region is not required for the IRS2-dependent regulation of glucose uptake. Bone morphogenetic protein 2-inducible kinase (BMP2K) binds to the INV region and contributes to IRS2-dependent invasion. Taken together, our data advance the mechanistic understanding of how IRS2 regulates invasion and reveal that IRS2 functions important for cancer can be independently targeted without interfering with the metabolic activities of this adaptor protein.

The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3K-mediated regulation of MYC

“…In previous studies, we and others identified a role for IRS2, but not IRS1, in the regulation of invasion, a property of tumor cells that facilitates the metastatic spread of cells to distant sites in the body. 21 , 52 CSCs have also been implicated in metastatic colonization by supporting the initiation of tumor growth in distant organs. 3 The combined ability of IRS2 to mediate signaling that supports both invasion and CSC function may explain the dominant role of IRS2 in metastatic progression.…”

IRS2 Amplification as a Predictive Biomarker in Response to Ceritinib in Small Cell Lung Cancer

“…[20][21][22] IRS2 enhances glucose metabolism and promotes migration, invasion, and metastasis in various type of tumors. 16,18,[23][24][25][26] However, it is not well known for clinical outcomes of the IRS2 expression in lung cancer progression, so we focused on IRS2 amplification and conducted various experiments to validate whether IRS2 amplification and/or expression is a therapeutic biomarker in metastatic SCLC.…”

VHL Ser65 mutations enhance HIF2α signaling and promote epithelial-mesenchymal transition of renal cancer cells

“…Of the hypoxia signaling, known HIFα-regulated genes include ADM [ 28 ], VEGFA [ 12 , 29 ], PDK3 [ 30 ], LOX [ 31 ], MXI1 [ 32 ], PDK1 [ 33 ], XPNPEP1 [ 34 ], SLC2A1 [ 34 ], IRS2 [ 35 ], and PFKFB3 [ 36 ], which have been shown to promote tumor growth and progression in various types of cancers. Previous reports showed that tumorigenesis is promoted via upregulation of glycolysis by ENO2 [ 37 ], PGK1 [ 38 ], ERO1A [ 39 ], P4HA1 [ 40 ], and IRS2 [ 41 ]. TGFBI is an extracellular matrix related oncogene that can lead to a significant enhancement of glycolysis for invasive tumor phenotype [ 42 ].…”