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标题：Hypoxic induction of AKAP12 variant 2 shifts PKA-mediated protein phosphorylation to enhance migration and metastasis of melanoma cells
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作者：Elizabeth C. Finger ; Laura Castellini ; Erinn B. Rankin 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：14
页码：4441-4446
DOI：10.1073/pnas.1418164112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceScaffold proteins can serve as critical focal points for association of signaling molecules and downstream pathways that regulate tumor growth and invasion. We demonstrate that low oxygen levels, common in solid tumors, can regulate expression of one member of the AKAP scaffold protein family, AKAP12, in melanoma. Genetic inactivation of AKAP12 leads to decreased migration, invasion, and tumor growth in a mouse model of melanoma. Mechanistically, we discovered a switch in protein kinase A (PKA)-regulated phosphorylations under hypoxia that are dependent on AKAP12 and show that PKA is the critical kinase regulating AKAP12-dependent cellular migration. These results provide novel insight into how the tumor microenvironment modulates signal transduction and biological responses through the regulation of a specific variant of the scaffold protein AKAP12. 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 protein can be regulated by the tumor microenvironment and further explains how a tumor cell can coordinate many critical signaling pathways that are essential for tumor growth through one individual scaffolding protein.
关键词：AKAP12 ; melanoma ; metastasis