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J. Biol. Chem., Vol. 275, Issue 22, 17024-17034, June 2, 2000
From the Departments of Signal transduction via protein kinase C (PKC) is
closely regulated by its subcellular localization. In response to
activation of cell-surface receptors, PKC is directed to the plasma
membrane by two membrane-targeting domains, namely the C1 and C2
regions. This is followed by the return of the enzyme to the cytoplasm, a process shown recently to require PKC autophosphorylation (Feng, X.,
and Hannun, Y. A. (1998) J. Biol. Chem. 273, 26870-26874). In the present study, we examined mechanisms of
translocation and reverse translocation and the role of
autophosphorylation in these processes. By visualizing the trafficking
of wild-type as well as mutant PKC
Regulation of Receptor-mediated Protein Kinase C Membrane
Trafficking by Autophosphorylation*
§,
**, and
Cell Biology and
Medicine, Duke University Medical Center, Durham, North Carolina
27710 and the ¶ Department of Biochemistry and Molecular Biology,
Medical University of South Carolina,
Charleston, South Carolina 29425
II in live cells, we demonstrated
that in response to cell-surface receptor activation, the function of the C1 region is required but not sufficient for recruitment of the
enzyme to the plasma membrane. The C2 region is also critical in
anchoring the enzyme to the plasma membrane. Furthermore, the inability
of a kinase-deficient PKC to undergo reverse translocation was restored
by the addition of intracellular calcium chelators, suggesting a role
for the C2 region in the persistent phase of translocation. On the
other hand, the inability of a C2 deletion mutant (C1 region intact) to
translocate in response to agonist was reversed in mutants lacking
kinase activity or by mutation of the Ser660
autophosphorylation site to alanine, suggesting that
autophosphorylation of this site is required for opposing the action of
the C2 region. Therefore, the membrane-targeting function of the C1
region is facilitated by the C2 region and appears to be opposed by
autophosphorylation. Taken together, these findings provide novel
evidence of the functional regulation of reversible PKC membrane
localization by autophosphorylation, and they show that the dynamic
translocation of PKC in response to agonists is tightly regulated in a
collaborative fashion by the C1 and C2 regions in balance with the
effects of autophosphorylation.
*
This work was supported in part by National Institutes of
Health Grant HL-43707.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Biochemistry and Molecular Biology, Medical University of South
Carolina, 171 Ashley Ave., Charleston, SC 29425. Tel.: 843-792-4321;
Fax: 843-792-4322; E-mail: hannun@musc.edu.
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