A Neuronal Form of the Cell Adhesion Molecule L1 Contains a Tyrosine-Based Signal Required for Sorting to the Axonal Growth Cone

Abstract

The neural cell adhesion molecule L1, which is present on axons and growth cones, plays a crucial role in the formation of major axonal tracts such as the corticospinal tract and corpus callosum. L1 is preferentially transported to axons and inserted in the growth cone membrane. However, how L1 is sorted to axons remains unclear. Tyr 1176 in the L1 cytoplasmic domain is adjacent to a neuron-specific alternatively spliced sequence, RSLE (Arg-Ser-Leu-Glu). The resulting sequence of YRSLE conforms to a tyrosine-based consensus motif (YxxL) for sorting of integral membrane proteins into specific cellular compartments. To study a possible role of the YRSLE sequence in L1 sorting, chick DRG neurons were transfected with human L1 cDNA that codes for full-length L1 (L1 FL ), a non-neuronal form of L1 that lacks the RSLE sequence (L1 ⌬RSLE ), mutant L1 with a Y1176A substitution (L1 Y1176A ), or L1 truncated immediately after the RSLE sequence (L1 ⌬C77 ). L1 FL and L1 ⌬C77 , both of which possess the YRSLE sequence, were expressed in the axonal growth cone and to a lesser degree in the cell body. In contrast, expression of both L1 ⌬RSLE and L1 Y1176A was restricted to the cell body and proximal axonal shaft. We also found that L1 ⌬RSLE and L1 Y1176A were integrated into the plasma membrane in the cell body after missorting. These data demonstrate that the neuronal form of L1 carries the tyrosinebased sorting signal YRSLE, which is critical for sorting L1 to the axonal growth cone.

Cleavage of L1 in Exosomes and Apoptotic Membrane Vesicles Released from Ovarian Carcinoma Cells

“…We previously reported that predominantly the neural form of L1 containing the RSLE form is recruited in spontaneously released vesicles (24). The RSLE motif facilitates interaction with the A2 chain of the clathrin adaptor AP-2 and affects the phosphorylation and endocytosis of L1 by creating an endocytic motif allowing clathrin-mediated internalization (49,50). Indeed, we found by reverse transcription-PCR that OVMz cells expressed the neural form of L1.…”

Translation of the cell adhesion molecule ALCAM in axonal growth cones – regulation and functional importance

“…ALCAM does not possess any sorting signals targeting the protein to the axonal compartment, such as found for CAML1 (Kamiguchi and Lemmon, 1998;Yap et al, 2008); we therefore asked whether ALCAM might be synthesized in the axon tip (growth cone). Translation in the axonal growth cone has been shown for approximately ten different proteins (Jung and Holt, 2011) and is required for the response to various guidance cues (Lin and Holt, 2007).…”

Activation of the MAPK Signal Cascade by the Neural Cell Adhesion Molecule L1 Requires L1 Internalization

“…Second, L1 adhesion may be regulated at the level of cell surface expression (17). The neuronal form of L1 contains an alternatively spliced exon encoding four amino acids (RSLE) within the L1CD (18), which contributes to a tyrosine based sorting/endocytosis motif (YRSL) (19). This sequence enables the L1CD to directly bind the 2 subunit of the adaptin complex AP-2, linking L1 to the clathrin-mediated endocytotic pathway (20).…”