PKA Cβ: a forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies

Taylor, Susan S.; Wallbott, Maximilian; Machal, Erik M F; Søberg, Kristoffer; Ahmed, Faihaa; Bruystens, Jessica; Vu, Lily; Baker, Blaine; Wu, Jian; Raimondi, Francesco; Ongeri, Elimelda Moige; Herberg, Friedrich W.; Skålhegg, Bjørn Steen

doi:10.1042/bcj20200867

Cited by 19 publications

(19 citation statements)

References 91 publications

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“…GRK2, also known as BARK, was also shown to play a role in the development of cardiovascular disease. PKA, a cAMP-dependent kinase, is involved in multiple signaling pathways, contributes to tau hyperphosphorylation, and has been implicated in progression of several neurodegenerative disorders, including AD, PD, and HD [ 49 , 67 , 68 , 69 , 70 ]. PKA was also shown to play roles in diabetes [ 70 ] and anxiety-related behavior [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

“…Using phosphorylation prediction programs, NetPhos (http://www.cbs.dtu.dk/services/ NetPhos, accessed 18 October 2019) and GPS (http://gps.biocuckoo.org/online.php, accessed 18 October 2019), we predicted the upstream kinases for each putative GFAP target residue (Supplementary Table S1 and Figure 3a). All of the implicated kinases (AKT2, ROCK1, BARK/GRK, and PKA), predicted to phosphorylate GFAP at the modified sites, had been previously implicated in AD pathogenesis or progression [45][46][47][48][49][50][51][52][53]. We therefore tested the effects of individual kinase knockdowns on protein aggregation in human neuroblastoma cells (SH-SY5Y-APP Sw ; Figure 3b,c) and human glioblastoma cells (T98G; Figure 3d,e), with or without siRNA-mediated knockdown.…”

Section: Identification Of Potential Kinases Mediating Gfap Phosphory...mentioning

confidence: 99%

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Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease

et al. 2022

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Glial fibrillary acidic protein (GFAP) is an intermediate filament structural protein involved in cytoskeleton assembly and integrity, expressed in high abundance in activated glial cells. GFAP is neuroprotective, as knockout mice are hypersensitive to traumatic brain injury. GFAP in cerebrospinal fluid is a biomarker of Alzheimer’s disease (AD), dementia with Lewy bodies, and frontotemporal dementia (FTD). Here, we present novel evidence that GFAP is markedly overexpressed and differentially phosphorylated in AD hippocampus, especially in AD with the apolipoprotein E [ε4, ε4] genotype, relative to age-matched controls (AMCs). Kinases that phosphorylate GFAP are upregulated in AD relative to AMC. A knockdown of these kinases in SH-SY5Y-APPSw human neuroblastoma cells reduced amyloid accrual and lowered protein aggregation and associated behavioral traits in C. elegans models of polyglutamine aggregation (as observed in Huntington’s disease) and of Alzheimer’s-like amyloid formation. In silico screening of the ChemBridge structural library identified a small molecule, MSR1, with stable and specific binding to GFAP. Both MSR1 exposure and GF AP-specific RNAi knockdown reduce aggregation with remarkably high concordance of aggregate proteins depleted. These data imply that GFAP and its phosphorylation play key roles in neuropathic aggregate accrual and provide valuable new biomarkers, as well as novel therapeutic targets to alleviate, delay, or prevent AD.

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Potential Kinases Mediating Gfap Phosphory...mentioning

confidence: 99%

Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease

et al. 2022

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“…They are myristylated and have the same number of residues (350 aa). Moreover, if one maps the 25 amino acid differences between Cα1 and Cβ1 (Figure 6) one finds that they localize primariy to the N-and C-terminal tails and to the regions in the core that flank these tails (Taylor et al 2021). Their catalytic residues are conserved so it is likely that these isoforms are regulated differently.…”

Section: Pka C-subunits and The Combinatorial Expansion Of Exonmentioning

confidence: 99%

The Tails of Protein Kinase A

et al. 2021

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PKA is a holoenzyme consisting of a regulatory (R) subunit dimer and two catalytic (C) subunits. There are two major families of C-subunits, C and C, and four functionally nonredundant R-subunits (RI, RI, RII, RII). In addition to binding to and being regulated by the R-subunits, the C-subunits are regulated by two tails-regions that each wrap around the N-and C-lobes of the kinase core. While the Ct-Tail is classified as an intrinsically disordered region (IDR), the Nt-Tail is dominated by a strong helix that is flanked by short IDRs. In contrast to the Ct-Tail, which is a conserved and highly regulated feature of all AGC kinases, the Nt-Tail has evolved more recently and is highly variable in vertebrates. Surprisingly and in contrast to the kinase core and the Ct-Tail, the entire Nt-tail is not conserved in non-mammalian PKAs. In particular, in humans C actually represents a large family of C-subunits that are highly variable in their Nt-Tail and also expressed in a highly tissue-specific manner. While we know so much about the C1 subunit, we know almost nothing about these C isoforms where C2 is highly expressed in lymphocytes and C3 and C4 isoforms account for ~50% of PKA signaling in brain. Based on recent disease mutations, the C proteins appear to be functionally important and non-redundant with the C isoforms. Imaging in retina also supports non-redundant roles for C as well as isoform-specific localization to mitochondria. This represents a new frontier in PKA signaling.

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“…In principle, however, there are many potential Ser/Thr protein kinase targets, 135 especially if one considers the many isoforms/splice variants such as with PKA Cβ. 136 It is thus likely that the proportion of Ser/Thr protein kinase inhibitors among approved drugs will increase as the field continues to mature. Hidaka and co-workers clearly established the druggability of ATP pockets of Ser/Thr protein kinases with their isoquinoline inhibitors.…”

Section: ■ Accelerating Kinase Inhibitor Discoverymentioning

confidence: 99%

“…The approval of imatinib initiated the development of a variety of tyrosine kinase inhibitors that are mostly used as anticancer therapeutics, and tyrosine and tyrosine-like kinases are more easily correlated with specific diseases. In principle, however, there are many potential Ser/Thr protein kinase targets, especially if one considers the many isoforms/splice variants such as with PKA Cβ . It is thus likely that the proportion of Ser/Thr protein kinase inhibitors among approved drugs will increase as the field continues to mature.…”

Section: Accelerating Kinase Inhibitor Discoverymentioning

confidence: 99%

Drugging the Undruggable: How Isoquinolines and PKA Initiated the Era of Designed Protein Kinase Inhibitor Therapeutics

Lorenz

Herberg

et al. 2021

Biochemistry

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In 1984, Japanese researchers led by the biochemist Hiroyoshi Hidaka described the first synthetic protein kinase inhibitors based on an isoquinoline sulfonamide structure (Hidaka et al. Biochemistry, 1984 Oct 9; 23(21): 5036–41. doi: 10.1021/bi00316a032). These led to the first protein kinase inhibitor approved for medical use (fasudil), an inhibitor of the AGC subfamily Rho kinase. With potencies strong enough to compete against endogenous ATP, the isoquinoline compounds established the druggability of the ATP binding site. Crystal structures of their protein kinase complexes, including with cAMP-dependent protein kinase (PKA), showed interactions that, on the one hand, could mimic ATP but, on the other hand, could be optimized for high potency binding, kinase selectivity, and diversification away from adenosine. They also showed the flexibility of the glycine-rich loop, and PKA became a major prototype for crystallographic and nuclear magnetic resonance (NMR) studies of protein kinase mechanism and dynamic activity control. Since fasudil, more than 70 kinase inhibitors have been approved for clinical use, involving efforts that progressively have introduced new paradigms of data-driven drug discovery. Publicly available data alone comprise over 5000 protein kinase crystal structures and hundreds of thousands of binding data. Now, new methods, including artificial intelligence techniques and expansion of protein kinase targeting approaches, together with the expiration of patent protection for optimized inhibitor scaffolds, promise even greater advances in drug discovery. Looking back to the time of the first isoquinoline hinge binders brings the current state-of-the-art into stark contrast. Appropriately for this Perspective article, many of the milestone papers during this time were published in Biochemistry (now ACS Biochemistry).

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PKA Cβ: a forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies

Cited by 19 publications

References 91 publications

Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease

Glial Fibrillary Acidic Protein: A Biomarker and Drug Target for Alzheimer’s Disease

The Tails of Protein Kinase A

Drugging the Undruggable: How Isoquinolines and PKA Initiated the Era of Designed Protein Kinase Inhibitor Therapeutics

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