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Vol. 12, Issue 3, 629-644, March 2001

Signaling Mediated by the Cytosolic Domain of Peptidylglycine -Amidating Monooxygenase

M. Rashidul Alam,^* Tami C. Steveson, Richard C. Johnson, Nils Bäck, Benjamin Abraham,^§ Richard E. Mains, and Betty A. Eipper

Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030-3401

The luminal domains of membrane peptidylglycine -amidating monooxygenase (PAM) are essential for peptide -amidation, and the cytosolic domain (CD) is essential for trafficking. Overexpression of membrane PAM in corticotrope tumor cells reorganizes the actin cytoskeleton, shifts endogenous adrenocorticotropic hormone (ACTH) from mature granules localized at the tips of processes to the TGN region, and blocks regulated secretion. PAM-CD interactor proteins include a protein kinase that phosphorylates PAM (P-CIP2) and Kalirin, a Rho family GDP/GTP exchange factor. We engineered a PAM protein unable to interact with either P-CIP2 or Kalirin (PAM-1/K919R), along with PAM proteins able to interact with Kalirin but not with P-CIP2. AtT-20 cells expressing PAM-1/K919R produce fully active membrane enzyme but still exhibit regulated secretion, with ACTH-containing granules localized to process tips. Immunoelectron microscopy demonstrates accumulation of PAM and ACTH in tubular structures at the trans side of the Golgi in AtT-20 cells expressing PAM-1 but not in AtT-20 cells expressing PAM-1/K919R. The ability of PAM to interact with P-CIP2 is critical to its ability to block exit from the Golgi and affect regulated secretion. Consistent with this, mutation of its P-CIP2 phosphorylation site alters the ability of PAM to affect regulated secretion.

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Corresponding author. E-mail: eipper{at}uchc.edu.the

Present addresses: ^* Laboratory of Oral Medicine, Building 30, Room 122, NIDCR, National Institutes of Health, 30 Convent Drive, Bethesda, MD 20892; Department of Neurosciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205; ^§Department of Neurology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205; Department of Anatomy, Institute of Biomedicine and Department of Basic Veterinary Sciences, University of Helsinki, Helsinki, Finland 00014.

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Molecular Biology of the Cell
Vol. 12, 629-644, March 2001
Copyright © 2001 by The American Society for Cell Biology

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