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Published online 8 August 2005. doi:10.1083/jcb.200506051
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 4, 595-605
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Article

 Transcytosis of NgCAM in epithelial cells reflects differential signal recognition on the endocytic and secretory pathways

Eric Anderson, Sandra Maday, Jeff Sfakianos, Michael Hull, Bettina Winckler, David Sheff, Heike Fölsch, and Ira Mellman

Department of Cell Biology, Ludwig Institute for Cancer Research, Yale University School of Medicine, New Haven, CT 06520

Correspondence to Ira Mellman: ira.mellman{at}yale.edu

NgCAM is a cell adhesion molecule that is largely axonal in neurons and apical in epithelia. In Madin-Darby canine kidney cells, NgCAM is targeted to the apical surface by transcytosis, being first inserted into the basolateral domain from which it is internalized and transported to the apical domain. Initial basolateral transport is mediated by a sequence motif (Y33RSL) decoded by the AP-1B clathrin adaptor complex. This motif is a substrate in vitro for tyrosine phosphorylation by p60src, a modification that disrupts NgCAM's ability to interact with clathrin adaptors. Based on the behavior of various NgCAM mutants, it appears that after arrival at the basolateral surface, the AP-1B interaction site is silenced by phosphorylation of Tyr33. This slows endocytosis and inhibits basolateral recycling from endosomes, resulting in NgCAM transcytosis due to a cryptic apical targeting signal in its extracellular domain. Thus, transcytosis of NgCAM and perhaps other membrane proteins may reflect the spatial regulation of recognition by adaptors such as AP-1B.

E. Anderson and S. Maday contributed equally to this paper.

E. Anderson's present address is HistoRx, Inc., New Haven, CT 06511.

B. Winckler's present address is Dept. of Neuroscience, University of Virginia Medical School, Charlottesville, VA 22908.

D. Sheff's present address is Dept. of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 522423.

H. Fölsch's present address is Dept. of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL 60208.

Abbreviations used in this paper: abd, ankyrin binding domain; ERM, ezrin-radixin-moesin; grr, glycine-rich region; LDLR, low density lipoprotein receptor; pIg-R, polymeric Ig receptor; prr, proline-rich region; shRNA, short hairpin RNA.


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