Defective PKA Signaling in Cushing's Syndrome

库欣综合征中 PKA 信号传导缺陷

• 批准号: 10582988
• 负责人: John D Scott
• 金额: $ 49.96万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582988
• 关键词: A kinase anchoring protein; Adrenal Cortex; Adrenal Gland Neoplasms; Adrenal Glands; Alleles; Amendment; Anabolism; Arginine; Back; Biochemical; Blood Circulation; Blood Glucose; Catalytic Domain; Cell Nucleus; Cells; Chronic; Clinical; Cushing Syndrome; Cushingoid facies; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Defect; Development; Diabetes Mellitus; Disease; Endocrine; Endocrine System Diseases; Enzyme Stability; Enzymes; Event; Exclusion; Exposure to; Female; Glucose; Holoenzymes; Hormones; Hydrocortisone; Hypertension; Island; Knock-in Mouse; Left; Lesion; Molecular; Mus; Mutation; Operative Surgical Procedures; Organ Size; Other Genetics; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Pituitary Neoplasms; Point Mutation; Proteins; Public Health; Radiation; Rosaniline Dyes; Sampling; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stains; Stress; Symptoms; Testing; Tissues; Variant; Weight Gain; Woman; adenoma; adrenal hyperplasia; blood pressure elevation; chemotherapy; comorbidity; disease-causing mutation; intracellular protein transport; men; mouse model; mutant; precision medicine; protein distribution; restoration; spatiotemporal; transmission process; virtual

ABSTRACT Cushing’s syndrome occurs when the adrenal glands release too much of the stress hormone cortisol. This endocrine disorder is naturally caused by adrenal or pituitary tumors and afflicts women five times more frequently than men. Chronic exposure to cortisol also increases blood glucose and elevates blood pressure. This proposal investigates the molecular pathogenesis of adrenal Cushing’s syndrome. This disease is often an outcome of defective cAMP signaling in the adrenal cortex. Advances in precision medicine have identified point mutations and insertions in protein kinase A catalytic subunits (PKAc) as drivers of this disease. The most prevalent mutant is PKAc-L205R, which is found in ~45% of Cushing’s patients. Other genetic lesions include PKAc-W196R. Both disease-causing mutations reside within a region of the kinase domain that interfaces with its regulatory subunits. This protein-protein interface is necessary for autoinhibition of kinase activity, but also directs the subcellular targeting of PKA holoenzymes through association with A kinase anchoring proteins (AKAPs). Our biochemical, cell-based, and clinical analyses infer that carrying a mutant allele of PKAc-L205R or W196R is sufficient to displace the kinase from normal subcellular sites of action in Cushing’s patients. This has led to a working hypothesis that losing spatiotemporal control of protein kinase A underlies adrenal Cushing’s syndrome. Aim 1 will test if i) restoration of PKA anchoring amends cortisol release, ii) identify which AKAPs coordinate cortisol biosynthesis and iii) considers an opposing premise that “substrate rewiring” of PKAc variants or altered enzyme stability drives Cushing’s syndrome. At first glance, the PKAc-L205R and PKAc-W196R mutants look virtually identical. Yet we have discovered that these are physiochemically distinct kinases that engage different cell signaling pathways. Analyses of patient tissue reveal that PKAc-L205R mobilizes the Hippo signaling pathway to control organ size. Conversely phenotypic profiling of adrenal-specific knock-in mice indicate that PKAc-W196R activates the ERK mitogenic kinase cascade. Aim 2 will evaluate i) if female PKAcWT/W196R mice are more prone to Cushing’s comorbidities, ii) test if PKAc-L205R engages the Hippo signaling cascade to drive cortisol hyperproduction and iii) ascertain if PKAc-W196R coordinates ERK signaling events to promote adrenal hyperplasia. This proposal explores two transformative ideas that will change how we think about Cushing’s syndrome. 1) Losing spatiotemporal control of protein kinase A underlies adrenal Cushing’s pathologies. 2) Adjacent and identical mutations in PKAc drive adrenal hyperplasia and cortisol hypersecretion in Cushing’s patients.

摘要

项目成果

AKAP Signaling Islands: Venues for Precision Pharmacology.

• DOI: 10.1016/j.tips.2020.09.007
• 发表时间: 2020-12
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Omar MH;Scott JD
• 通讯作者: Scott JD

Classification of Cushing's syndrome PKAc mutants based upon their ability to bind PKI

• DOI: 10.1042/bcj20230183
• 发表时间: 2023-06-01
• 期刊: BIOCHEMICAL JOURNAL
• 影响因子: 4.1
• 作者: Omar，Mitchell H.;Kihiu，Maryanne;Scott，John D.
• 通讯作者: Scott，John D.

Proximity biotinylation to define the local environment of the protein kinase A catalytic subunit in adrenal cells.

• DOI: 10.1016/j.xpro.2022.101992
• 发表时间: 2023-03-17
• 期刊: STAR protocols
• 作者: Omar MH;Lauer SM;Lau HT;Golkowski M;Ong SE;Scott JD
• 通讯作者: Scott JD

Mislocalization of protein kinase A drives pathology in Cushing's syndrome.

• DOI: 10.1016/j.celrep.2022.111073
• 发表时间: 2022-07-12
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Omar, Mitchell H.;Byrne, Dominic P.;Jones, Kiana N.;Lakey, Tyler M.;Collins, Kerrie B.;Lee, Kyung-Soon;Daly, Leonard A.;Forbush, Katherine A.;Lau, Ho-Tak;Golkowski, Martin;McKnight, G. Stanley;Breault, David T.;Lefrancois-Martinez, Anne-Marie;Martinez, Antoine;Eyers, Claire E.;Baird, Geoffrey S.;Ong, Shao-En;Smith, F. Donelson;Eyers, Patrick A.;Scott, John D.
• 通讯作者: Scott, John D.

Neurotensin as a source of cyclic AMP and co-mitogen in fibrolamellar hepatocellular carcinoma.

神经降压素作为纤维板层肝细胞癌中环磷酸腺苷和共丝裂原的来源。

• DOI: 10.18632/oncotarget.27149
• 发表时间: 2019
• 期刊: Oncotarget
• 作者: Riehle,KimberlyJ;Kenerson,HeidiL;Riggle,KevinM;Turnham,Rigney;Sullivan,Kevin;Bauer,Renay;Scott,JohnD;Yeung,RaymondS
• 通讯作者: Yeung,RaymondS