Protein kinase A (PKA)- and protein kinase C-phosphorylated glia maturation factor promotes the catalytic activity of PKA.
We observed previously that glia maturation factor (GMF), a 17-kDa brain protein, is rapidly phosphorylated in astrocytes following stimulation by phorbol ester, and that protein kinase A (PKA)-phosphorylated GMF is a potent inhibitor of extracellular signal-regulated kinase (ERK) and enhancer of p38; both are subfamilies of mitogen-activated protein (MAP) kinase, suggesting GMF as a bifunctional regulator of the MAP kinase cascades. In the current report, we present evidence that PKA-phosphorylated GMF also promotes (11-fold) the catalytic activity of PKA itself, resulting in a positive feedback loop. Furthermore, GMF phosphorylated by protein kinase C (PKC), but not by casein kinase II or p90 ribosomal S6 kinase, also activates PKA (7-fold). It appears that the mutual augmentation of GMF and PKA, and the stimulating effect of PKC, both serve to maximize the influence of PKA on the regulation of MAP kinase cascades by GMF. Using synthetic peptide fragments containing putative phosphorylation sites of GMF, we demonstrate that PKA is capable of phosphorylating threonine 26 and serine 82, whereas PKC, p90 ribosomal S6 kinase, and casein kinase II, can phosphorylate serine 71, threonine 26, and serine 52, respectively. The generation of various phospho-isoforms of GMF may explain its modulation of signal transduction at multiple locations.
Zaheer
A
A
Department of Neurology, Division of Neurochemistry and Neurobiology, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52242, USA.
Lim
R
R
D000595:Amino Acid Sequence; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020904:Glia Maturation Factor; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
D020904:Glia Maturation Factor; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C