Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism
Gary K L Chan,
Yeonjoo C Hwang,
Rebecca R B Wolber,
Krushna C Patra,
Heidi L Kenerson,
Raymond S. Yeung,
Danielle L Swaney,
Nevan J. Krogan,
Rigney E Turnham,
John D Scott,
Kimberly J Riehle,
John D Gordan
Posted 16 Apr 2021
bioRxiv DOI: 10.1101/2021.04.16.438110
Posted 16 Apr 2021
Genetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms are poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved signaling outputs driven by diverse genetic changes that activate PKA in human cancer, including melanoma and fibrolamellar carcinoma (FLC). We define two consensus networks of effectors downstream of PKA in cancer models. One is centered on RAS/MAPK components, and a second involves Aurora Kinase A (AURKA). We find that AURKA stabilizes c-MYC and n-MYC protein levels and expression programs in PKA-dependent tumor models, in part via a positive feedback loop mediated by the oncogenic kinase PIM2. This process can be suppressed by conformation-disrupting AURKA inhibitors such as CD-532. Our findings elucidate two independent mechanisms of PKA-driven tumor cell growth and offer insight into drug targets for study in FLC and other PKA-dependent malignancies.
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