Defining A‐Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA‐RI)

Autenrieth, Karolin; Bendzunas, N. George; Bertinetti, Daniela; Kennedy, Eileen J.

doi:10.1002/cbic.201500632

Cited by 15 publications

(16 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite that heterodimers of RIα and RIβ have been reported to form PKAI, most PKAI holoenzymes are thought to contain either RIα or RIβ homodimers ( 24 , 32 , 33 ). The R subunit isoforms also associate with different sets of proteins, locating the PKA holoenzymes to different subcellular compartments ( 34 – 36 ). All R subunits share the same overall architecture ( 37 ).…”

Section: The Pka R Subunit Is a Major Intracellular Camp Receptormentioning

confidence: 99%

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

Søberg

Skålhegg

2018

Front. Endocrinol.

View full text Add to dashboard Cite

Assembly of multi enzyme complexes at subcellular localizations by anchoring- and scaffolding proteins represents a pivotal mechanism for achieving spatiotemporal regulation of cellular signaling after hormone receptor targeting [for review, see (1)]. In the 3′ 5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase (PKA) signaling pathway it is generally accepted that specificity is secured at several levels. This includes at the first level stimulation of receptors coupled to heterotrimeric G proteins which through stimulation of adenylyl cyclase (AC) forms the second messenger cAMP. Cyclic AMP has several receptors including PKA. PKA is a tetrameric holoenzyme consisting of a regulatory (R) subunit dimer and two catalytic (C) subunits. The R subunit is the receptor for cAMP and compartmentalizes cAMP signals through binding to cell and tissue-specifically expressed A kinase anchoring proteins (AKAPs). The current dogma tells that in the presence of cAMP, PKA dissociates into an R subunit dimer and two C subunits which are free to phosphorylate relevant substrates in the cytosol and nucleus. The release of the C subunit has raised the question how specificity of the cAMP and PKA signaling pathway is maintained when the C subunit no longer is attached to the R subunit-AKAP complex. An increasing body of evidence points toward a regulatory role of the cAMP and PKA signaling pathway by targeting the C subunits to various C subunit binding proteins in the cytosol and nucleus. Moreover, recent identification of isoform specific amino acid sequences, motifs and three dimensional structures have together provided new insight into how PKA at the level of the C subunit may act in a highly isoform-specific fashion. Here we discuss recent understanding of specificity of the cAMP and PKA signaling pathway based on C subunit subcellular targeting as well as evolution of the C subunit structure that may contribute to the dynamic regulation of C subunit activity.

show abstract

Section: The Pka R Subunit Is a Major Intracellular Camp Receptormentioning

confidence: 99%

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

Søberg

Skålhegg

2018

Front. Endocrinol.

View full text Add to dashboard Cite

show abstract

“…Four R subunits (RIα, RIβ, RIIα and RIIβ) and six principal C subunits (Cα1, Cα2, Cβ1–4) are expressed in humans, and cell type-specific expression of different subunits changes the composition and thereby intracellular localization and substrate specificity of PKA isoforms 2 . R subunits serve as cAMP receptors and facilitate the spatial localization of PKA within the cell by binding different A-Kinase anchoring proteins (AKAPs) 3 . The subunit RIβ is primarily expressed in the brain 4,5 , with the highest levels of expression in the cerebral cortex and hypothalamus 6 .…”

Section: Introductionmentioning

confidence: 99%

Variants inPRKAR1Bcause a neurodevelopmental disorder with autism spectrum disorder,apraxia, and insensitivity to pain

Marbach

Stoyanov

Erger

et al. 2020

Preprint

View full text Add to dashboard Cite

Purpose: We characterize the phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder, who carry heterozygous missense-variants of the PRKAR1B gene. Methods: Variants of PRKAR1B were identified by single-exome or trio-exome analysis. We contacted the families and physicians of the six individuals in order to collect clinical and phenotypic information. Results: PRKAR1B encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA), and is predominantly expressed in the central nervous system. Recent studies of patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B, and in vivo studies of the murine ortholog demonstrated altered hippocampal function and reduced neurogenic inflammation and long-term nociceptive pain in R1β-deficient mice. In our study, de novo origin of the PRKAR1B-variants could be confirmed in five out of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p. Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia has been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. Conclusion: Our study provides strong evidence for a novel, PRKAR1B-related neurodevelopmental disorder.

show abstract

“…The majority of AKAPs bind to the PKA-RII isoform due to structural differences between PKA-RI and PKA-RII. However, some AKAPs such D-AKAP-1/2 recognize the PKA-RI isoform (Autenrieth et al 2016). Since the presence of the AKAP helix is the only requirement for an AKAP protein, there is a large number of proteins that serve as an AKAP acting in many different subcellular contexts.…”

Section: The Camp Signalling Pathwaymentioning

confidence: 99%

The Popeye domain containing gene family encoding a family of cAMP-effector proteins with important functions in striated muscle and beyond

Swan

Gruscheski

Boland

et al. 2019

J Muscle Res Cell Motil

View full text Add to dashboard Cite

The Popeye domain containing (POPDC) gene family encodes a novel class of membrane-bound cyclic AMP effector proteins. POPDC proteins are abundantly expressed in cardiac and skeletal muscle. Consistent with its predominant expression in striated muscle, Popdc1 and Popdc2 null mutants in mouse and zebrafish develop cardiac arrhythmia and muscular dystrophy. Likewise, mutations in POPDC genes in patients have been associated with cardiac arrhythmia and muscular dystrophy phenotypes. A membrane trafficking function has been identified in this context. POPDC proteins have also been linked to tumour formation. Here, POPDC1 plays a role as a tumour suppressor by limiting c-Myc and WNT signalling. Currently, a common functional link between POPDC's role in striated muscle and as a tumour suppressor is lacking. We also discuss several alternative working models to better understand POPDC protein function.

show abstract

Defining A‐Kinase Anchoring Protein (AKAP) Specificity for the Protein Kinase A Subunit RI (PKA‐RI)

Cited by 15 publications

References 18 publications

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

The Molecular Basis for Specificity at the Level of the Protein Kinase a Catalytic Subunit

Variants inPRKAR1Bcause a neurodevelopmental disorder with autism spectrum disorder,apraxia, and insensitivity to pain

The Popeye domain containing gene family encoding a family of cAMP-effector proteins with important functions in striated muscle and beyond

Contact Info

Product

Resources

About