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Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

ABSTRACT: 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 cancer. We define two consensus networks of effectors downstream of PKA in cancer models including melanoma and fibrolamellar carcinoma [FLC]. 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 designate drug targets for study in FLC and other PKA-dependent malignancies.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Urinary Bladder Cancer,Thyroid Gland Follicular Carcinoma,Skin Melanoma

SUBMITTER: John Gordan

LAB HEAD: John Dozier Gordan

PROVIDER: PXD025508 | Pride | 2023-02-09

REPOSITORIES: Pride

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			Action	DRS
	639V-PRKAR1-annotated-results.txt	Txt
	639V-older-MIBsFinalComparisons.txt	Txt
	639VPRKACA_MIBs_mqpar.xml	Xml
	639VPRKACA_MIBs_msms_original.txt	Txt
	639VPRKACA_phos_evidence.txt	Txt

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