Disease relevance of PRKAR2B

• DRA (down-regulated in adenoma) is expressed in the gut and encodes a protein with sequence homology to anion transporters, whereas PRKAR2B encodes a regulatory subunit for protein kinase A. Both genes map within 450 kb from D7S496, making them functionally and positionally relevant candidates for CLD [1].
• By using truncated NH2-terminal RII beta fusion proteins expressed in Escherichia coli and the mitotic protein kinase p34cdc2 isolated from HeLa cells or starfish oocytes, we investigated the in vitro phosphorylation of RII beta by these kinases [2].
• The infection with MT-RII beta and treatment with CdCl2 brought about growth arrest in HL-60 human leukemia and Ki-ras-transformed NIH 3T3 clone DT cells in monolayer culture with no sign of toxicity [3].
• Fusion gene constructs, containing RII beta 5'-flanking sequences and the bacterial CAT structural gene, were transfected into NB2a neuroblastoma cells and CHO cells [4].
• We determined whether ASO to either the RI alpha or RII beta subunit altered the cAMP-mediated growth of HCT116 and LoVo human colon cancer cells [5].

Psychiatry related information on PRKAR2B

• The distribution of the regulatory (RII beta) subunits of type II cAMP-dependent protein kinase in cortical and subcortical areas was examined in human control and Alzheimer's disease (AD) brains [6].

High impact information on PRKAR2B

• We observed that RI alpha decreased within 24 h of 8-Cl-cAMP treatment, that RII beta increased after as few as 3 h of treatment, and that PKA catalytic activity remained unchanged during 48 h of 8-Cl-cAMP treatment [7].
• We propose that p85 anchors RII beta to the Golgi apparatus of human lymphoblasts and thereby defines the Golgi substrate targets most accessible to phosphorylation by C subunit [8].
• Identification of a high affinity binding protein for the regulatory subunit RII beta of cAMP-dependent protein kinase in Golgi enriched membranes of human lymphoblasts [8].
• Point mutation of the autophosphorylation site or in the nuclear location signal causes protein kinase A RII beta regulatory subunit to lose its ability to revert transformed fibroblasts [9].
• In contrast to phosphorylation by casein kinase II or the cAMP-dependent protein kinase catalytic subunit, phosphorylation of RII beta by mitotic kinases impaired its interaction with a well-known RII-anchoring protein, the neuronal microtubule-associated protein 2 [2].

Biological context of PRKAR2B

• Furthermore, in situ hybridization to metaphase chromosomes physically mapped PRKAR2B to band q22 on chromosome 7 [10].
• Previous data from the CEPH database and our present RFLP data were used to construct a six-point local framework map including PRKAR1B and a seven-point framework map including PRKAR2B [10].
• Mapping of the regulatory subunits RI beta and RII beta of cAMP-dependent protein kinase genes on human chromosome 7 [10].
• This phosphorylation site matches the consensus sequence X(T/S)PX(K/R) for p34cdc2 recognition and belongs to a well-conserved sequence found in all RII beta sequences known to date [2].
• Boundaries for the RII beta tethering domain were mapped to residues 392-413 by scanning mutagenesis [11].

Anatomical context of PRKAR2B

• A Kinase Anchor Proteins (AKAPs) are enriched in forebrain neurons and have distinct high affinity binding domains for the regulatory subunit (RII beta) of PKAII beta and components of the dendritic cytoskeleton [11].
• Deletion of N-terminal residues 27-48 generated a truncated RII beta-binding protein that partitions equally between the cytosol and detergent-insoluble fractions of HEK293 cells [11].
• CAT plasmids containing these RII beta sequences showed 12- and 16-fold increased CAT activity in the NB2a and CHO cells, respectively, compared to the basic CAT vector [12].
• In conclusion, 1,25-(OH)2D3 attenuates both PKAI formation and PKAI-stimulated iodide uptake in rat thyroid FRTL-5 cells by increasing the level of RII beta without altering the other PKA subunit levels [13].
• A highly acidic C-terminal region mediates the binding of RII beta (and cAMP-dependent protein kinase II beta), whereas a positively charged N-terminal segment contains structural features that are essential for the association of AKAP 75 with the cytoskeleton and/or intracellular membranes [14].

Associations of PRKAR2B with chemical compounds

• The putative site for phosphorylation by the mitotic kinases is Thr-69 in the NH2-terminal domain of RII beta [2].
• The potential regulatory significance of the phosphorylation of this site on the interaction with microtubule-associated protein 2 and other RII-anchoring proteins and the physiological relevance of this cyclin B/p34cdc2 kinase-catalyzed modification of RII beta (or phosphorylation by other proline-directed protein kinases) are discussed [2].
• Western blot analysis of 1,25-(OH)2D3-treated cells revealed a 4-fold increase in the cytosolic amount of the PKA regulatory subunit RII beta, whereas no changes were detected in the regulatory subunits RI alpha and RII alpha or the catalytic (C) subunit [13].
• The predicted protein contains 418 amino acids including the start methionine, and the estimated mol wt of human RII beta is 53,856 [15].
• During the development of preovulatory follicles, tonic levels of FSH (and steroid) induce expression of aromatase, the LH receptor, and RII beta in a coordinate manner [16].

Physical interactions of PRKAR2B

• Mutagenesis, recombinant protein expression, and physicochemical characterization were used to investigate the structural basis for the homodimerization and AKAP75 binding activities of RII beta [17].
• Evidently, large hydrophobic side chains of Leu13 and Phe36 play pivotal roles in stabilizing RII beta-RII beta interactions [17].

Other interactions of PRKAR2B

• In contrast, cells transfected with a construct encoding 249 amino acids from the central and C-terminal regions of AKAP 75 produced an RII beta-binding protein (apparent Mr = 45,000) that was exclusively cytosolic [14].
• Messenger RNA levels for the PKA RII alpha and RII beta as well as PKC beta were not affected by HCMV infection [18].
• Steady-state levels of snk and sgk mRNA are induced rapidly (within a few hours) by FSH in granulosa cells prior to the appearance of transcripts for aromatase, LH receptor, and RII beta (T. Alliston and J. S. Richards, in preparation) [16].
• A similar protein kinase profile as that shown by 8-Cl-cAMP treatment was observed in cells infected with the human RII beta retroviral vector: the 48-kDa RI of PKI decreased and the 52- and 54-kDa RII associated with PKII increased as compared with uninfected control cells [19].
• Association of deficient type II protein kinase A activity with aberrant nuclear translocation of the RII beta subunit in systemic lupus erythematosus T lymphocytes [20].

Analytical, diagnostic and therapeutic context of PRKAR2B

• We approached the structure-function analysis of RII beta by using site-directed mutagenesis [9].
• Northern blot analyses showed a similar increase in RII beta mRNA in cells treated for 12 h with 1,25-(OH)2D3 (10 nM), and RII beta mRNA increased further to 10-fold above control cell level after 96 h of incubation [13].
• In the human lymphoblastic cell line KE 37, Northern blot analysis with cDNA probes for human regulatory subunits RII alpha RII beta of the cAMP-dependent protein kinase (A-kinase) type II and immunoblotting or immunoprecipitation studies with several antibodies directed against RII alpha and RII beta show that these two isoforms are expressed [21].
• This study supports the conclusion that the mobilities of human RII subunits (RII alpha, RII beta) on SDS-PAGE are reversed in contrast with those of other species such as rat and bovine.(ABSTRACT TRUNCATED AT 400 WORDS)[22]
• We hereby present the molecular cloning of rat cDNAs for RII beta, as well as full-length human cDNAs for RII beta and RI alpha [23].

References