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J Biol Chem, Vol. 273, Issue 25, 15533-15539, June 19, 1998
From the Molecular Biology and Virology Laboratory, The Salk
Institute for Biological Studies, La Jolla, California 92037
C-type natriuretic peptide (CNP) is a newly
discovered factor that stimulates vasorelaxation and inhibits cell
proliferation. Natriuretic peptide receptor-B (NPR-B) is the primary
signaling molecule for CNP. Recently, the guanylyl cyclase activity of
NPR-B was shown to correlate with its phosphorylation state, and it was
suggested that receptor dephosphorylation is a mechanism of desensitization. We now report the identification and characterization of the major NPR-B phosphorylation sites. Mutagenesis and comigration studies using synthetic phosphopeptides were employed to identify five
residues (Ser-513, Thr-516, Ser-518, Ser-523, and Ser-526) within the
kinase homology domain that are phosphorylated when NPR-B is expressed
in human 293 cells. Mutation of any of these residues to alanine
reduced the receptor's phosphorylation state and
CNP-dependent guanylyl cyclase activity. The reductions
were not explained by decreases in receptor protein level as indicated by immunoblot analysis and determinations of cyclase activity in the
absence of CNP or in the presence of detergent. Elimination of all of
the phosphorylation sites resulted in a completely dephosphorylated receptor whose CNP-dependent cyclase activity was decreased
by >90%. However, unlike NPR-A, the dephosphorylated receptor was not
completely unresponsive to hormone. Finally, two additional residues
(Gly-521 and Ser-522) were identified that when mutated to alanine
reduced the overall phosphorylation state and hormone responsiveness of
the receptor without abolishing the phosphorylation of a specific site.
These data indicate that phosphorylation of the kinase homology domain
is a critical event in the regulation of NPR-B.
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