Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated cDNA molecules encoding a protein with the characteristic sequence elements that are conserved between the catalytic domains of protein kinases. This protein is apparently a serine/threonine kinase and is most closely related to the amino-terminal half of the ribosomal protein S6 kinase II first characterized in Xenopus eggs (42% overall identity and 56% identity in the predicted catalytic domain). However, it clearly differs from S6 kinase II in that it has only one, rather than two predicted catalytic domains and a deduced molecular mass of 59,109 Da. We propose that is may be more related to, or identical, with, the mitogen-inducible S6 kinase of molecular mass 65-70 kDa described in mammalian liver, mouse 3T3 cells and chicken embryos. Remarkable structural features of the cDNA-encoded polypeptide are a section rich in proline, serine and threonine residues that resemble the multiphosphorylation domains of glycogen synthase and phosphorylase kinase alpha subunit, and a characteristic tyrosine residue in the putative nucleotide-binding glycine cluster which, by analogy to cdc2 kinase, is a potential tyrosine phosphorylation site.
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PMID:cDNA encoding a 59 kDa homolog of ribosomal protein S6 kinase from rabbit liver. 169 10

We have cloned and sequenced human cDNAs encoding the complete phosphorylase kinase alpha subunit muscle isoform (alpha M). The predicted polypeptide is highly similar to the sequence known from rabbit muscle but lacks a major part of its multiphosphorylation domain, including the main phosphorylation site for cAMP-dependent protein kinase (PKA). Analysis of this region by reverse-transcribed polymerase chain reaction (RT-PCR) in several human and rabbit tissues demonstrates that it is subject to elaborate differential mRNA splicing. Amino acids 1012-1024 of the full-length rabbit sequence, including the major PKA phosphorylation site, and amino acids 1025-1041, which harbor at least one endogenous phosphorylation site, can be deleted from the predicted polypeptide individually or in combination. Molecules lacking one or both of these segments constitute a major part of the alpha M subunit population in many rabbit tissues and constitute the vast majority in all human tissues analyzed. Similar, tissue-dependent differential splicing events could be detected by RT-PCR in the human alpha subunit isoform from liver (alpha L). The expression of the differentially spliced alpha M subtypes differs markedly between corresponding human and rabbit tissues. Sequence divergence in this region is particularly high, not only between the muscle and liver isoforms, but also between alpha M sequences from four different animal species. Moreover, a duplication of the exon encoding the main PKA phosphorylation site was discovered in the mouse. Thus, the multiphosphorylation domain of the phosphorylase kinase alpha subunit isoforms is subject to pronounced structural variation not only between different tissues of one organism via differential splicing, but also in the course of evolution.
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PMID:The multiphosphorylation domain of the phosphorylase kinase alpha M and alpha L subunits is a hotspot of differential mRNA processing and of molecular evolution. 822 41

Glycogen storage disease (GSD) type IX is a rare disease of variable clinical severity affecting primarily the liver tissue. Individuals with liver phosphorylase b kinase (PhK) deficiency (GSD IX) can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth with considerable variation in clinical severity. PhK is a cAMP-dependent protein kinase that phosphorylates the inactive form of glycogen phosphorylase, phosphorylase b, to produce the active form, phosphorylase a. PhK is a heterotetramer; the alpha 2 subunit in the liver is encoded by the X-linked PHKA2 gene. About 75% of individuals with liver PhK deficiency have mutations in the PHKA2 gene; this condition is also known as X-linked glycogenosis (XLG). Here we report the variability in clinical severity and laboratory findings in 12 male patients from 10 different families with X-linked liver PhK deficiency caused by mutations in PHKA2. We found that there is variability in the severity of clinical features, including hypoglycemia and growth. We also report additional PHKA2 variants that were identified in 24 patients suspected to have liver PhK deficiency. The basis of the clinical variation in GSDIX due to X-linked PHKA2 gene mutations is currently not well understood. Creating systematic registries, and collecting longitudinal data may help in better understanding of this rare, but common, glycogen storage disorder.
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PMID:Clinical and Molecular Variability in Patients with PHKA2 Variants and Liver Phosphorylase b Kinase Deficiency. 2828 41