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J Biol Chem, Vol. 274, Issue 49, 34646-34656, December 3, 1999

The Novel Kinase Peptidylglycine -Amidating Monooxygenase Cytosolic Interactor Protein 2 Interacts with the Cytosolic Routing Determinants of the Peptide Processing Enzyme Peptidylglycine -Amidating Monooxygenase

From the Departments of Neuroscience and Physiology, The Johns Hopkins University School of Medicine, Baltimore Maryland 21205 and the ^§ Departments of Surgery and Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201

The cytosolic domain of the peptide-processing integral membrane protein peptidylglycine -amidating monooxygenase (PAM; EC 1.14.17.3) contains multiple signals determining its subcellular localization. Three PAM cytosolic interactor proteins (P-CIPs) were identified using the yeast two hybrid system (Alam, M. R., Caldwel, B. D., Johnson, R. C., Darlington, D. N., Mains, R. E., and Eipper, B. A. (1996) J. Biol. Chem. 271, 28636-28640); the partial amino acid sequence of P-CIP2 suggested that it was a protein kinase. In situ hybridization and immunocytochemistry show that P-CIP2 is expressed widely throughout the brain; PAM and P-CIP2 are expressed in the same neurons. Based on subcellular fractionation, the 47-kDa P-CIP2 protein is mostly cytosolic. P-CIP2 is a highly selective kinase, phosphorylating the cytosolic domain of PAM, but not the corresponding region of furin or carboxypeptidase D. Although P-CIP2 interacts with stathmin, it does not phosphorylate stathmin. Site-directed mutagenesis, phosphoamino acid analysis, and use of synthetic peptides demonstrate that PAM-Ser⁹⁴⁹ is the major site phosphorylated by P-CIP2. Based on both in vitro binding experiments and co-immunoprecipitation from cell extracts, P-CIP2 interacts with PAM proteins containing the wild type cytosolic domain, but not with mutant forms of PAM whose trafficking is disrupted. P-CIP2, through its highly selective phosphorylation of a key site in the cytosolic domain of PAM, appears to play a critical role in the trafficking of this protein.

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