IGPR-1 is phosphorylated on the immunoreceptor tyrosine-based motif, stimulates AKT pathway and supports melanoma growth

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ABSTRACT Melanoma is a lethal form of skin cancer that impacts one out of every five Americans and ranks as the fifth most prevalent cancer among men and women in the United States. Immunoglobulin (Ig) and Proline-rich Receptor-1 (IGPR-1, also called TMIGD2/CD28H) is closely related to immune checkpoint, CD28/PDL1 family receptors. It controls important cellular processes including, immune cell regulation, cell-cell adhesion, mechanosensing, autophagy, and angiogenesis, and its activity is associated with multiple human malignancies. However, the role and signaling mechanism of IGPR-1 in melanoma remains largely undefined. Here, we report that IGPR-1 is mutated or upregulated in nearly 13% of melanoma and its pro-tumor signaling in melanoma cells is mediated by phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM) tyrosine (Y222). IGPR-1 is phosphorylated at Y222 in human melanoma and cell culture. Phosphorylation of Y222 is context-dependent and is catalyzed by EGFR and Src kinase. Inhibition of EGFR by pharmacological and shRNA strategies inhibited phosphorylation of Y222, whereas stimulation with EGF promoted phosphorylation of Y222 in vivo and recombinant active EGFR catalyzed its phosphorylation in an in vitro kinase assay. In vivo co-immunoprecipitation and in vitro GST-pull-down assays demonstrated that phospho-Y222 facilitates the binding of IGPR-1 with the SH2 domain-containing proteins, SHC1 and SHP2. IGPR-1 stimulates multiple key signal transduction pathways relevant to tumorigenesis, including AKT, mTOR, and MAPK. Mutation of Y222 blocked IGPR-1-mediated activation of AKT and MAPK leading to inhibition of 3D-spheroid tumor growth. By investigating the immunoreceptor tyrosine-based motif signaling of IGPR-1, this study uncovers new findings that could have significant diagnostic and therapeutic implications for melanoma.

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