The neural adhesion molecule L1 is phosphorylated on tyrosine and serine residues

Heiland, Petra C.; Hertlein, Birgit; Traub, Otto; Griffith, Lee S.; Schmitz, Brigitte

doi:10.1097/00001756-199611040-00053

Cited by 13 publications

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“…Indeed, it has been demonstrated that the cytoplasmic domain of L1 is phosphorylated on tyrosine, possibly on Try 1176 (Heiland et al, 1996). Because the tyrosine in the sorting motif has to be in a nonphosphorylated state for the signal to be active (Boll et al, 1996;Ohno et al, 1996), the YRSLE sequence might have dual roles (sorting signal or SH2 binding) depending on the phosphorylation state of the tyrosine.…”

Section: Discussionmentioning

confidence: 99%

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

1998

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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.

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Section: Discussionmentioning

confidence: 99%

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

1998

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“…Ethanol also inhibits type 5 metabotropic glutamate receptor-induced calciumdependent chloride currents by promoting protein kinase C phosphorylation (Minami et al,i998). It is conceivable that the ethanol sensitivity of Li is also influenced by posttransiational modifications. Li is phosphoryiated at specific serine and tyrosine residues, and phosphorylation modifies Li-mediated neurite outgrowth (Sadoul et al, 1989;Heiland et al, 1996;Wong et ai., 1996a,b;Zisch et al, 1997). Tyrosine phosphorylation of neurofascin, a member of the Li family of adhesion proteins, inhibits its binding to ankyrin and increases its lateral mobility (Garver et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Ethanol‐Sensitive and Insensitive Fibroblast Cell Lines Expressing Human L1

Wilkemeyer

Charness

1998

Journal of Neurochemistry

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Ethanol inhibits Li-mediated cell-cell adhesion in fibroblast cell lines stably transfected with human Li. Here we show that this action of ethanol is present in only a subset of transfected NIH/3T3 and L cell clonal cell lines. All Li-expressing cell lines had higher levels of cell adhesion than cell lines transfected with empty vector. In all ethanol-sensitive cell lines, Li -mediated adhesion was inhibited by ethanol (IC 50 5-iO mM), 2 mM butanol, but not 5 mM pentanol. In contrast, ethanolinsensitive cell lines were not inhibited by up to 200 mM ethanol, 2 mM butanol, or 5 mM pentanol. Ethanol sensitivity or insensitivity was a stable property of each cell line and was not associated with differences in electrophoretic mobility, abundance, or cell surface localization of Li. Fab fragments prepared from anti-Li polyclonal antisera inhibited cell adhesion only in the ethanol-sensitive cell lines. These data suggest that Li may exist in an alcohol-sensitive or an alcohol-insensitive state that may be governed by host cell factors. Key Words: Ethyl alcohol-Fetal alcohol syndrome-Cell adhesion molecule, Li -Cell transfection. J. Neurochem. 71, 2382Neurochem. 71, -239i (1998.The immunoglobulin neural cell adhesion molecule (N-CAM) Li plays a fundamental role in nervous system development (Hortsch, 1996). Li is expressed on axons and growth cones and binds to Li molecules on adjacent cells, components of the extracellular matrix, and cytoskeletal elements. Activation of Li initiates a signaling cascade involving the fibroblast growth factor receptor (Williams et al., i 994) and pp6O c-srr (1g nelzi et al., 1994), leading to changes in growth cone morphology and neurite outgrowth (Lemmon et al., 1989; Kamiguchi and Lemmon, i997). Two isoforms of Li are generated by alternate splicing of a 12-base pair segment in the cytoplasmic domain encoding the amino acids arginine, serine, leucine, and glutamic acid (RSLE) (Reid and Hemperly, i992). The RSLE-positive isoform is expressed predominantly in the CNS, and the RSLE domain may help sort Li to the axon growth cone . Homophilic binding of human Li is mediated by the second immunoglobulin domain of the extracellular portion of the molecule (Zhao and Siu, 1995); deletion of the cytoplasmic domain does not reduce adhesiveness (Hortsch et al., i995;Wong et al., 1995). Mutations in the gene for Li are associated with a spectrum of neurodevelopmental disorders characterized by mental retardation and combinations of aphasia, shuffling gait, adducted thumbs, spastic paraparesis, agenesis of the corpus callosum, hydrocephalus, pyramidal tract hypoplasia, and cerebellar dysplasia (Fransen et al., 1995).We noted previously a similarity in the neuropathology of Li mutations and fetal alcohol syndrome (FAS) (Ramanathan et al., 1996). Based on this observation, we studied the effects of ethanol on cell-cell interactions mediated by Li. Pharmacologically relevant concentrations of ethanol inhibited cell-cell adhesion in NG1O8-i5 cells treated with OP-l (an inducer of Li and...

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“…In embryonic day-13 chicken retina, both the L1 family member neuron-glia cell adhesion molecule (Ng-CAM) and EphB2 are phosphorylated on tyrosine. In support of a broad occurrence of in vivo tyrosine phosphorylation of L1 family proteins is the finding that L1 is also phosphorylated on tyrosine in 8-day old mouse brain (Heiland et al 1996). Furthermore, phosphoamino-acid analysis of metabolically labeled L1 preparations from cultured mice cerebellar neurons suggests that the extent of L1 phosphorylation on tyrosine is comparable to the extent of serine phosphorylation.…”

Section: ªCrosstalkº Between the Ephb2 Receptor And Neural Cell Adhesmentioning

confidence: 87%

The Eph family: a multitude of receptors that mediate cell recognition signals

Zisch

Pasquale

1997

Cell and Tissue Research

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The Eph receptor tyrosine kinases are emerging as molecules that guide the migration of cells and growth cones during embryonic development. Based on their concentration in embryonic regions containing growing neuronal processes, the Eph receptors were suspected early on to have a role in regulating aspects of axon growth. The most distinctive role of the Eph receptors appears to be their ability to mediate cell-cell repulsion through the binding of a ligand on an adjacent cell surface. The repulsive interactions are presumably mediated by transient receptor activation at the boundaries of complementary regions of high ligand or receptor expression. In contrast, overlapping expression patterns may regulate cell adhesion and cytoskeletal organization with possible consequences on the overall growth and fasciculation of neuronal processes. A notable feature of Eph receptor signaling is that, upon receptor binding, responses may also be elicited in the ligand-expressing cells. A better understanding of Eph receptor function requires the elucidation of their signaling properties. Recent evidence suggests a functional interaction between the Eph receptor EphB2 and neural cell adhesion molecules of the L1 family, which have well-recognized roles in the formation of neuronal projections. Only a few cytoplasmic signaling molecules that bind to the activated Eph receptors have been identified. Several of these molecules are known to transduce signals regulating cytoskeletal organization and neurite outgrowth. It is currently unclear why there is a need for fourteen distinct Eph receptor genes, many of which appear to encode several variant forms with distinct functional properties, but it is tempting to speculate that such diversity is necessary to refine the spatial organization of embryonic structures.

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The neural adhesion molecule L1 is phosphorylated on tyrosine and serine residues

Cited by 13 publications

References 0 publications

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

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

Characterization of Ethanol‐Sensitive and Insensitive Fibroblast Cell Lines Expressing Human L1

The Eph family: a multitude of receptors that mediate cell recognition signals

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