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¹ Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
² Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
³ Department of Ophthalmology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
⁴ Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
⁵ Macromolecular Structural Analysis Facility, University of Kentucky, Lexington, KY 40536
⁶ Department of Cell Biology, Harvard Medical School, Boston, MA 02115
⁷ The Center for Blood Research, Harvard Medical School, Boston, MA 02115

Address correspondence to Vance Lemmon, Department of Neurosciences, Case Western Reserve University School of Medicine, Rm. E661, 2109 Adelbert Rd., Cleveland, OH 44106-4975. Tel.: (216) 368-3039. Fax: (216) 368-4650. E-mail: vance{at}cwru.edu

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.

Key Words: IGSF protein; cell adhesion; growth cones; endocytosis; tyrosine-based sorting motifs

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