Inhibition of cGMP-dependent protein kinase II by its own splice isoform.
cGMP- and cAMP-dependent protein kinases (cGK I, cGK II, and cAK) are important mediators of many signaling pathways that increase cyclic nucleotide concentrations and ultimately phosphorylation of substrates vital to cellular functions. Here we demonstrate a novel mRNA splice isoform of cGK II arising from alternative 5' splicing within exon 11. The novel splice variant encodes a protein (cGK II Delta(441-469)) lacking 29 amino acids of the cGK II Mg-ATP-binding/catalytic domain, including the conserved glycine-rich loop consensus motif Gly-x-Gly-x-x-Gly-x-Val which interacts with ATP in the protein kinase family of enzymes. cGK II Delta(441-469) has no intrinsic enzymatic activity itself, however, it antagonizes cGK II and cGK I, but not cAK. Thus, the activation and cellular functions of cGK II may be determined not only by intracellular cGMP levels but also by alternative splicing which may regulate the balance of expression of cGK II versus its own inhibitor, cGK II Delta(441-469).
Gambaryan
Stepan
S
Institute of Clinical Biochemistry and Pathobiochemistry, Medical University Clinic, Josef Schneider Strasse 2, Wuerzburg D-97080, Germany. gambarya@klin-biochem.uni-wuerzburg.de
Palmetshofer
Alois
A
Glazova
Margarita
M
Smolenski
Albert
A
Kristjansson
Gunnar Ingi
GI
Zimmer
Michael
M
Lohmann
Suzanne M
SM
D016475:3T3 Cells; D020121:5' Untranslated Regions; D000255:Adenosine Triphosphate / Q000378:metabolism; D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D020134:Catalytic Domain; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005822:Genetic Vectors; D005998:Glycine / Q000737:chemistry; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014018:Tissue Distribution; D014162:Transfection
D020121:5' Untranslated Regions; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D012313:RNA; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; C569729:PRKG2 protein, human; C569720:Prkg1 protein, mouse; C569730:Prkg2 protein, mouse; C569732:Prkg2 protein, rat; D006152:Cyclic GMP; D005998:Glycine