L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1

Andrew W. Schaefer, Yoshimasa Kamei, Hiroyuki Kamiguchi, Eric V. Wong, Iris Rapoport, Tomas Kirchhausen, Carol M. Beach, Gary Landreth, Sandra K. Lemmon, Vance Lemmon

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

Dynamic regulation of the cell surface expression of adhesion molecules is an important mechanism for controlling neuronal growth cone motility and guidance. Clathrin-mediated vesicular internalization of L1 via the tyrosine-based endocytosis motif YRSL regulates adhesion and signaling by this Ig superfamily molecule. Here, we present evidence that tyrosine-1176 (Y1176) of the YRSL motif is phosphorylated in vivo. The nonreceptor tyrosine kinase (p60src) is implicated in L1-mediated neurite outgrowth, and we find that p60src phosphorylates Y1176 in vitro. Phosphorylation of Y1176 prevents L1 binding to AP-2, an adaptor required for clathrin-mediated internalization of L1. mAb 74-5H7 recognizes the sequence immediately NH2-terminal to the tyrosine-based motif and binds L1 only when Y1176 is dephosphorylated. 74-5H7 identifies a subset of L1 present at points of cell-cell contact and in vesicle-like structures that colocalize with an endocytosis marker. L1-L1 binding or L1 cross-linking induces a rapid increase in 74-5H7 immunoreactivity. Our data suggest a model in which homophilic binding or L1 cross-linking triggers transient dephosphorylation of the YRSL motif that makes L1 available for endocytosis. Thus, the regulation of L1 endocytosis through dephosphorylation of Y1176 is a critical regulatory point of L1-mediated adhesion and signaling.

Original languageEnglish (US)
Pages (from-to)1223-1232
Number of pages10
JournalJournal of Cell Biology
Volume157
Issue number7
DOIs
StatePublished - Jun 24 2002

Keywords

  • Cell adhesion
  • Endocytosis
  • Growth cones
  • IGSF protein
  • Tyrosine-based sorting motifs

ASJC Scopus subject areas

  • Cell Biology

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    Schaefer, A. W., Kamei, Y., Kamiguchi, H., Wong, E. V., Rapoport, I., Kirchhausen, T., Beach, C. M., Landreth, G., Lemmon, S. K., & Lemmon, V. (2002). L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1. Journal of Cell Biology, 157(7), 1223-1232. https://doi.org/10.1083/jcb.200203024