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(Circulation Research. 2006;98:846.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Embryonic Growth-Associated Protein Is One Subunit of a Novel N-Terminal Acetyltransferase Complex Essential for Embryonic Vascular Development

Janet M. Wenzlau, Pamela J. Garl, Peter Simpson, Kurt R. Stenmark, James West, Kristin B. Artinger, Raphael A. Nemenoff, Mary C.M. Weiser-Evans

From the Departments of Renal Medicine (R.A.N., M.C.M.W.-E.), Cell and Developmental Biology (K.B.A., M.C.M.W.-E.), Craniofacial Biology (P.S., K.B.A.), Pediatrics (J.M.W., P.J.G., K.R.S., M.C.M.W.-E.), and Cardiovascular Pulmonary Research (J.W.), University of Colorado Health Sciences Center, Denver.

Correspondence to Mary Weiser-Evans, PhD, Departments of Renal Medicine and Cell and Developmental Biology, Campus Box C281, University of Colorado Health Sciences Center, University of Colorado Cancer Center, 4200 E Ninth Ave, Denver, CO 80262. E-mail mary.weiser{at}uchsc.edu

N-terminal protein acetylation, catalyzed by N-terminal acetyltransferases (NATs) recognizing distinct N-terminal sequences, is gaining recognition as an essential regulator of normal cell function, but little is known of its role in vertebrate development. We previously cloned a novel gene, embryonic growth-associated protein (EGAP), the expression of which is associated with rapid vascular smooth muscle cell proliferation during development. We show herein EGAP is the mammalian/zebrafish homologue of yeast Mak10p, one subunit of the yeast NatC complex, and describe the cloning of its binding partners Mak3 and Mak31. The EGAP NAT forms a functional complex in mammalian cells, is evolutionarily conserved, and developmentally regulated. It is widely but not ubiquitously expressed during early zebrafish development but undetectable in later developmental stages. We demonstrate EGAP- and Mak3-deficient zebrafish fail to develop because of, in part, decreased cell proliferation, increased apoptosis, and poor blood vessel formation contributing to embryonic lethality. We examined the role of target of rapamycin (TOR), a highly conserved protein kinase controlling cell growth, as a physiological target of EGAP NAT acetylation. Compared with controls, TOR expression and signaling is significantly reduced in EGAP morphants. Pharmacological inhibition of TOR with rapamycin phenocopied the EGAP morpholino oligonucleotide-induced growth and vessel defects. Overexpression of constitutively active TOR rescued EGAP morphants, suggesting TOR is a direct or indirect endogenous substrate of the EGAP NAT complex. These data suggest the EGAP NAT complex is an essential regulatory enzyme controlling the function of a subset of proteins required for embryonic growth control and vessel development.

Key Words: EGAP • TOR • N-terminal acetyltransferase • vascular development • vascular cell proliferation

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