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J Biol Chem, Vol. 274, Issue 8, 4807-4815, February 19, 1999

Functional Regulation of G₁₆ by Protein Kinase C

Anna M. Aragay and Michael W. Quick^§

From the  Centro de Biologia Molecular, Facultad de Ciencias, Universidad Autonoma de Madrid, Canto Blanco, 28049 Madrid, Spain and the ^§ Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0021

Recent evidence demonstrates that the  subunits of some heterotrimeric GTP-binding proteins (G proteins) are subject to modification by protein kinase C (PKC). For the family of G proteins that activate the phospholipase C/inositol trisphosphate/calcium/PKC pathway, such modification could result in G protein autoregulation. To examine the potential regulation of members of the G_q family by PKC phosphorylation, we expressed the thyrotropin-releasing hormone (TRH) receptor in combination with G_q, G₁₁, G₁₄, G₁₅, or G₁₆ in Xenopus oocytes and examined the regulation of signaling by PKC activators and inhibitors. For G₁₆ and G₁₅, the two family members of hematopoietic lineage, PKC activators reduce both the magnitude and the time course of TRH-mediated responses; PKC inhibitors have the opposite effect. The PKC-mediated effects are evident in measurements of GTPase activity, suggesting that the regulation is occurring early in the signaling pathway. In vivo phosphorylation experiments demonstrate that G₁₆ is a substrate for PKC modification. By comparison, G_q is not phosphorylated by PKC in vivo, and oocytes expressing G_q are not functionally modulated by PKC. Repeated TRH stimulation of oocytes expressing G₁₆ mimics the effects of PKC activators, and this functional regulation is correlated with an increase in G₁₆ phosphorylation. A mutant G₁₆ with four consensus PKC phosphorylation sites removed is not phosphorylated in vivo, and TRH responses mediated through the mutant are not regulated by PKC. These results demonstrate that signaling involving hematopoietic G proteins is subject to PKC-mediated autoregulation, at least in part, by phosphorylation of the G protein  subunit.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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