L1 sticks around

杨柳

The cell adhesion molecule (CAM) L1 is important for the growth of axons during neuronal development〞mutations in L1 cause birth defects and neurological disorders. Although its extracellular domain mediates cell-to-cell adhesion, the cytoplasmic domain of L1 determines the stickiness of this CAM by regulating its rate of internalization, according to new results from Schaefer et al. on page 1223.- T0 Y5 T! f, g8 z& B6 \

# r! B' f- x8 k1 r7 Y5 zThe new report shows that phosphorylation of the cytoplasmic domain makes L1 more adhesive by preventing its endocytosis. The residue Tyr1176, which is specific to the neuronal isoform of L1, was phosphorylated in vitro by the nonreceptor tyrosine kinase p60src. In vivo, phosphorylation of L1 prevented its endocytosis by inhibiting its interaction with the clathrin- associated AP-2 complex. Homophilic binding to L1 on a neighboring cell caused its dephosphorylation, which should promote endocytosis. As predicted, unphosphorylated L1 was found at sites of cell contact and in cytoplasmic vesicles.
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' }+ X6 h, @# H" t9 q+ Y) QA second article in this issue, by Dickson et al. (page 1105), demonstrates that this same AP-2–binding domain also interacts with the cytoskeletal protein ezrin. Disrupting L1 interaction with ezrin family members promoted axon branching, indicating that the interaction normally stabilizes engagement of the plasma membrane and the cytoskeleton.% ^* z! ?6 @! ]7 M  B: v; N( A

4 j$ B" Y2 e. u. |It will be interesting to determine whether phosphorylation of L1 also influences its binding to ezrin, revealing a simple molecular switch for regulation of L1 interaction partners. In this scenario, L1 at the front of the growth cone is phosphorylated, possibly by a src family kinase. Interaction with L1 in a nearby cell results in binding to ezrin and mediates forward movement of the growth cone. The migration places L1 at the back of the growth cone, where it may be subject to phosphatases and internalized in vesicles that carry it back to the front of the growth cone, where the cycle repeats.(Axonal branching increases when L1 does )