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Identification and characterization of novel mutations in the human gene encoding the catalytic subunit Calpha of protein kinase A (PKA).

ABSTRACT: The genes PRKACA and PRKACB encode the principal catalytic (C) subunits of protein kinase A (PKA) C? and C?, respectively. C? is expressed in all eukaryotic tissues examined and studies of C? knockout mice demonstrate a crucial role for C? in normal physiology. We have sequenced exon 2 through 10 of PRKACA from the genome of 498 Norwegian donors and extracted information about PRKACA mutations from public databases. We identified four interesting nonsynonymous point mutations, Arg45Gln, Ser109Pro, Gly186Val, and Ser263Cys, in the C?1 splice variant of the kinase. C? variants harboring the different amino acid mutations were analyzed for kinase activity and regulatory (R) subunit binding. Whereas mutation of residues 45 and 263 did not alter catalytic activity or R subunit binding, mutation of Ser(109) significantly reduced kinase activity while R subunit binding was unaltered. Mutation of C? Gly(186) completely abrogated kinase activity and PKA type I but not type II holoenzyme formation. Gly(186) is located in the highly conserved DFG motif of C? and mutation of this residue to Val was predicted to result in loss of binding of ATP and Mg(2+), which may explain the kinetic inactivity. We hypothesize that individuals born with mutations of Ser(109) or Gly(186) may be faced with abnormal development and possibly severe disease.

SUBMITTER: Soberg K

PROVIDER: S-EPMC3325940 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Identification and characterization of novel mutations in the human gene encoding the catalytic subunit Calpha of protein kinase A (PKA).

Søberg Kristoffer K Larsen Anja C V AC Diskar Mandy M Backe Paul H PH Bjørås Magnar M Jahnsen Tore T Laerdahl Jon K JK Rognes Torbjørn T Herberg Friedrich W FW Skålhegg Bjørn S BS

PloS one 20120413 4

The genes PRKACA and PRKACB encode the principal catalytic (C) subunits of protein kinase A (PKA) Cα and Cβ, respectively. Cα is expressed in all eukaryotic tissues examined and studies of Cα knockout mice demonstrate a crucial role for Cα in normal physiology. We have sequenced exon 2 through 10 of PRKACA from the genome of 498 Norwegian donors and extracted information about PRKACA mutations from public databases. We identified four interesting nonsynonymous point mutations, Arg45Gln, Ser109Pr ...[more]

PMID: 22514673

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Project description:Bronchopulmonary neuroendocrine tumours (BP-NETs) comprise a large spectrum of tumours including typical carcinoids (TCs), atypical carcinoids (ACs), large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) that exhibit considerably different biological aggressiveness and clinical behaviours. The phosphatidylinositol-3-kinase α catalytic subunit (PIK3CA) gene is known to be involved in the pathogenesis of several types of human cancers through gene amplification, deletions or somatic missense mutations within the helical and catalytic domains. However, the PIK3CA gene status in BP-NETs has yet to be explored. This study aimed to investigate the PIK3CA gene status in a large series of BP-NETs by direct gene sequencing and to analyse its correlation with the main clinicopathological parameters. To the best of our knowledge, we demonstrated for the first time a high frequency of somatic missense mutations (23.2%) in the PIK3CA gene in a series of 190 BP-NETs, including 75 TCs, 23 ACs, 17 LCNECs and 75 SCLCs. The frequency of the PIK3CA gene mutation in the kinase domain was higher (17.9%) than that in the helical domain (5.3%). When the mutational status of the PIK3CA gene was compared with the main clinical and pathological characteristics of the BP-NET patients, we found a significant association between PIK3CA gene mutations and BP-NET histology (p=0.011). Interestingly, the frequency of PIK3CA gene mutations increased with the biological aggressiveness of all BP-NETs, except LCNECs. In conclusion, our results suggest that PIK3CA gene mutations may play a key role in tumourigenesis and aggressiveness of BP-NETs. The PIK3CA gene may represent a favourable candidate for an effective therapeutic strategy in the treatment of patients with BP-NETs.

Dataset Information

Identification and characterization of novel mutations in the human gene encoding the catalytic subunit Calpha of protein kinase A (PKA).

Publications

Identification and characterization of novel mutations in the human gene encoding the catalytic subunit Calpha of protein kinase A (PKA).

Similar Datasets

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