Mislocalization of protein kinase A drives pathology in Cushing’s syndrome

Omar, Mitchell H.; Byrne, Dominic P.; Jones, KennethL.; 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.; Lefrançois‐Martinez, Anne‐Marie; Martinez, Antoine; Eyers, Claire E.; Baird, Geoffrey S.; Ong, Shao‐En; Smith, F. Donelson; Scott, John D.

doi:10.1016/j.celrep.2022.111073

Cited by 26 publications

(30 citation statements)

References 65 publications

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“…This protocol describes the specific steps to label proteins proximal to a miniTurbo-tagged protein kinase A catalytic subunit (PKAc-miniTurbo) in NCI-H295R adrenal cells. 3 Slight variations of this protocol have also been used for labeling proteins associated with AKAP18 variants in HEK cells and PKAc fusion proteins in AML12 hepatocytes. 2 …”

Section: Before You Beginmentioning

confidence: 99%

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

Omar¹,

Lauer²,

Lau³

et al. 2023

STAR Protocols

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Section: Before You Beginmentioning

confidence: 99%

“…These mass spectrometry datasets and identifiers are also listed in the original Cell Reports paper: Omar et al. 3 All data reported in this paper will be shared by the lead contact upon request.…”

Section: Data and Code Availabilitymentioning

confidence: 99%

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

Omar¹,

Lauer²,

Lau³

et al. 2023

STAR Protocols

Self Cite

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“…Alterations in the spatial localization are involved in most cellular biological processes, such as nucleocytoplasmic shuttling of p38 [ 98 ] and endocytic uptake of receptor tyrosine kinase [ 99 ]. Mislocalization of kinases is frequently associated with cellular dysfunction and diseases, including neurodegeneration, cancer and metabolic disorders [ 100 ]. Therefore, a tight control of kinase localization is an important regulatory component of cell physiology.…”

Section: Potential Strategies In Kinase Spatial Assaymentioning

confidence: 99%

Mapping the Protein Kinome: Current Strategy and Future Direction

Hou

Liu²

2023

Cells

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The kinome includes over 500 different protein kinases, which form an integrated kinase network that regulates cellular phosphorylation signals. The kinome plays a central role in almost every cellular process and has strong linkages with many diseases. Thus, the evaluation of the cellular kinome in the physiological environment is essential to understand biological processes, disease development, and to target therapy. Currently, a number of strategies for kinome analysis have been developed, which are based on monitoring the phosphorylation of kinases or substrates. They have enabled researchers to tackle increasingly complex biological problems and pathological processes, and have promoted the development of kinase inhibitors. Additionally, with the increasing interest in how kinases participate in biological processes at spatial scales, it has become urgent to develop tools to estimate spatial kinome activity. With multidisciplinary efforts, a growing number of novel approaches have the potential to be applied to spatial kinome analysis. In this paper, we review the widely used methods used for kinome analysis and the challenges encountered in their applications. Meanwhile, potential approaches that may be of benefit to spatial kinome study are explored.

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“…In contrast, study of the functional effects of the somatic PRKACA mutations, especially L205R, in adrenal adenomas shows that the L205R mutation alters the ability of the Cα subunits to be regulated by the regulatory subunits, leading to constitutive, cAMP-independent signaling ( 101 , 102 , 130 , 135 ). The L205R and W196R mutations also appear to exclude the mutant holoenzymes from their AKAP anchors, allowing them to diffuse indiscriminately throughout the cell, producing phosphorylation of non-physiologic PKA substrates ( 135 , 136 ).…”

Section: Wide Variation In the Biology And Clinical Features Of Camp-...mentioning

confidence: 99%

“…The continued application of dedicated phosphoproteomic approaches is highly likely to identify additional candidates ( 143 ). Such efforts are just beginning to pay off in cancer generally, and for the cAMP-pathway cancers in particular ( 136 , 137 , 144 ). Abnormal PKA action in cancer has the potential to produce two broad types of phosphorylation abnormalities: (1) increased phosphorylation of normally-physiologic substrates and (2) phosphorylation of new (hence, non-physiologic/pathologic) substrates.…”

Section: Wide Variation In the Biology And Clinical Features Of Camp-...mentioning

confidence: 99%

The cAMP-signaling cancers: Clinically-divergent disorders with a common central pathway

Bolger¹

2022

Front. Endocrinol.

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The cAMP-signaling cancers, which are defined by functionally-significant somatic mutations in one or more elements of the cAMP signaling pathway, have an unexpectedly wide range of cell origins, clinical manifestations, and potential therapeutic options. Mutations in at least 9 cAMP signaling pathway genes (TSHR, GPR101, GNAS, PDE8B, PDE11A, PRKARA1, PRKACA, PRKACB, and CREB) have been identified as driver mutations in human cancer. Although all cAMP-signaling pathway cancers are driven by mutation(s) that impinge on a single signaling pathway, the ultimate tumor phenotype reflects interactions between five critical variables: (1) the precise gene(s) that undergo mutation in each specific tumor type; (2) the effects of specific allele(s) in any given gene; (3) mutations in modifier genes (mutational “context”); (4) the tissue-specific expression of various cAMP signaling pathway elements in the tumor stem cell; and (5) and the precise biochemical regulation of the pathway components in tumor cells. These varying oncogenic mechanisms reveal novel and important targets for drug discovery. There is considerable diversity in the “druggability” of cAMP-signaling components, with some elements (GPCRs, cAMP-specific phosphodiesterases and kinases) appearing to be prime drug candidates, while other elements (transcription factors, protein-protein interactions) are currently refractory to robust drug-development efforts. Further refinement of the precise driver mutations in individual tumors will be essential for directing priorities in drug discovery efforts that target these mutations.

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Mislocalization of protein kinase A drives pathology in Cushing’s syndrome

Cited by 26 publications

References 65 publications

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

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

Mapping the Protein Kinome: Current Strategy and Future Direction

The cAMP-signaling cancers: Clinically-divergent disorders with a common central pathway

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