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J. Biol. Chem., Vol. 276, Issue 20, 16960-16968, May 18, 2001
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From the the § Department of Veterans Affairs,
Nashville, Tennessee 37212-2637 and the Protein phosphatase 2A (PP2A) is postulated to be
involved in the dephosphorylation of G protein-coupled receptors. In
the present study, we demonstrate that the carboxyl terminus of CXCR2 physically interacts with the PP2A core enzyme, a dimer formed by PP2Ac
and PR65, but not with the PP2Ac monomer, suggesting direct interaction
of the receptor with PR65. The integrity of a sequence motif in the C
terminus of CXCR2, KFRHGL, which is conserved in all CC and CXC
chemokine receptors, is required for the receptor binding to the PP2A
core enzyme. CXCR2 co-immunoprecipitates with the PP2A core enzyme in
HEK293 cells and in human neutrophils. Overexpression of dominant
negative dynamin 1 (dynamin 1 K44A) in CXCR2-expressing cells blocks
the receptor association with the PP2A core enzyme, and an
internalization-deficient mutant form of CXCR2 (I323A,L324A)
also exhibits impaired association with the PP2A core enzyme,
suggesting that the receptor internalization is required for the
receptor binding to PP2A. A phosphorylation-deficient mutant of CXCR2
(331T), which has previously been shown to undergo internalization in
HEK293 cells, binds to an almost equal amount of the PP2A core enzyme
in comparison with the wild-type CXCR2, suggesting that the interaction
of the receptor with PP2A is phosphorylation-independent. The
dephosphorylation of CXCR2 is reversed by treatment of the cells with
okadaic acid. Moreover, pretreatment of the cells with okadaic acid
increases basal phosphorylation of CXCR2 and attenuates CXCR2-mediated
calcium mobilization and chemotaxis. Taken together, these data
indicate that PP2A is involved in the dephosphorylation of CXCR2. We
postulate that this interaction results from direct binding of the
regulatory subunit A (PR65) of PP2A to the carboxyl terminus of CXCR2
after receptor sequestration and internalization.
Phosphorylation-independent Association of CXCR2 with the Protein
Phosphatase 2A Core Enzyme*
,,, and§¶
Department of
Cancer Biology, Vanderbilt University School of Medicine,
Nashville, Tennessee 37212-2175
*
This work was supported by a career scientist grant from the
Department of Veterans Affairs (to A. R.), by NCI, National Institutes of Health, Grant CA 34590 (to A. R.), and Vanderbilt-Ingram Cancer Center Grant CA68485.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.
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