Protein Kinase Signaling Networks Driven by Oncogenic Gq/11 in Uveal Melanoma Identified by Phosphoproteomic and Bioinformatic Analyses.

Michael D Onken, Petra Erdmann-Gilmore, Qiang Zhang, Kisan Thapa, Emily King, Kevin M Kaltenbronn, Sarah E Noda, Carol M Makepeace, Dennis Goldfarb, Özgün Babur, R Reid Townsend, Kendall J Blumer

Molecular & cellular proteomics : MCP 2023 Nov

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Metastatic uveal melanoma (UM) patients typically survive only 2 to 3 years because effective therapy does not yet exist. Here, to facilitate the discovery of therapeutic targets in UM, we have identified protein kinase signaling mechanisms elicited by the drivers in 90% of UM tumors: mutant constitutively active G protein α-subunits encoded by GNAQ (Gq) or GNA11 (G11). We used the highly specific Gq/11 inhibitor FR900359 (FR) to elucidate signaling networks that drive proliferation, metabolic reprogramming, and dedifferentiation of UM cells. We determined the effects of FR on the proteome and phosphoproteome of UM cells as indicated by bioinformatic analyses with CausalPath and site-specific gene set enrichment analysis. We found that inhibition of oncogenic Gq/11 caused deactivation of PKC, Erk, and the cyclin-dependent kinases CDK1 and CDK2 that drive proliferation. Inhibition of oncogenic Gq/11 in UM cells with low metastatic risk relieved inhibitory phosphorylation of polycomb-repressive complex subunits that regulate melanocytic redifferentiation. Site-specific gene set enrichment analysis, unsupervised analysis, and functional studies indicated that mTORC1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 drive metabolic reprogramming in UM cells. Together, these results identified protein kinase signaling networks driven by oncogenic Gq/11 that regulate critical aspects of UM cell biology and provide targets for therapeutic investigation. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Michael D Onken, Petra Erdmann-Gilmore, Qiang Zhang, Kisan Thapa, Emily King, Kevin M Kaltenbronn, Sarah E Noda, Carol M Makepeace, Dennis Goldfarb, Özgün Babur, R Reid Townsend, Kendall J Blumer. Protein Kinase Signaling Networks Driven by Oncogenic Gq/11 in Uveal Melanoma Identified by Phosphoproteomic and Bioinformatic Analyses. Molecular & cellular proteomics : MCP. 2023 Nov;22(11):100649