Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells

Proceedings of the National Academy of Sciences of the United States of America
Elizabeth C FingerAmato J Giaccia

Abstract

Scaffold proteins are critical hubs within cells that have the ability to modulate upstream signaling molecules and their downstream effectors to fine-tune biological responses. Although they can serve as focal points for association of signaling molecules and downstream pathways that regulate tumorigenesis, little is known about how the tumor microenvironment affects the expression and activity of scaffold proteins. This study demonstrates that hypoxia, a common element of solid tumors harboring low oxygen levels, regulates expression of a specific variant of the scaffold protein AKAP12 (A-kinase anchor protein 12), AKAP12v2, in metastatic melanoma. In turn, through a kinome-wide phosphoproteomic and MS study, we demonstrate that this scaffolding protein regulates a shift in protein kinase A (PKA)-mediated phosphorylation events under hypoxia, causing alterations in tumor cell invasion and migration in vitro, as well as metastasis in an in vivo orthotopic model of melanoma. Mechanistically, the shift in AKAP12-dependent PKA-mediated phosphorylations under hypoxia is due to changes in AKAP12 localization vs. structural differences between its two variants. Importantly, our work defines a mechanism through which a scaffold prote...Continue Reading

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Citations

Sep 20, 2015·Cellular Signalling·Alessandro DemaEnno Klussmann
Sep 30, 2016·Nucleic Acids Research·Stuart G JarrettJohn A D'Orazio
Jun 10, 2017·Current Osteoporosis Reports·Rachelle W JohnsonAmato J Giaccia
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Oct 13, 2020·Frontiers in Oncology·Zhiwei ShaoJianmin Zhang
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Dec 10, 2020·Experimental Hematology & Oncology·Hongying ZhangHui Hua
Jul 16, 2021·Nature Communications·Eui Jung MoonAmato J Giaccia

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