Gil, O.D. et al. Ankyrin binding mediates L1CAM interactions with static components of the cytoskeleton and inhibits retrograde movement of L1CAM on the cell surface. J. Cell Biol. 162, 719-730

Dept. of Pharmacology and Biological Chemistry, Box 1215, One Gustave L. Levy Place, Mt. Sinai School of Medicine, New York, NY 10029, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 09/2003; 162(4):719-30. DOI: 10.1083/jcb.200211011
Source: PubMed


The function of adhesion receptors in both cell adhesion and migration depends critically on interactions with the cytoskeleton. During cell adhesion, cytoskeletal interactions stabilize receptors to strengthen adhesive contacts. In contrast, during cell migration, adhesion proteins are believed to interact with dynamic components of the cytoskeleton, permitting the transmission of traction forces through the receptor to the extracellular environment. The L1 cell adhesion molecule (L1CAM), a member of the Ig superfamily, plays a crucial role in both the migration of neuronal growth cones and the static adhesion between neighboring axons. To understand the basis of L1CAM function in adhesion and migration, we quantified directly the diffusion characteristics of L1CAM on the upper surface of ND-7 neuroblastoma hybrid cells as an indication of receptor-cytoskeleton interactions. We find that cell surface L1CAM engages in diffusion, retrograde movement, and stationary behavior, consistent with interactions between L1CAM and two populations of cytoskeleton proteins. We provide evidence that the cytoskeletal adaptor protein ankyrin mediates stationary behavior while inhibiting the actin-dependent retrograde movement of L1CAM. Moreover, inhibitors of L1CAM-ankyrin interactions promote L1CAM-mediated axon growth. Together, these results suggest that ankyrin binding plays a crucial role in the anti-coordinate regulation of L1CAM-mediated adhesion and migration.

Download full-text


Available from: Dan P Felsenfeld, Oct 28, 2014
  • Source
    • "In addition, phosphorylation of L1 increases its association with doublecortin, which is important for neuronal migration (126), and is downstream of MAP kinase pathways (127). This suggests that ERK-dependent signaling may promote neurite growth through downregulation of L1 and ankyrin binding (128, 129). These observations highlight the diversity of the L1 gene family, and the need for more research into how other components of the L1 family interact at the level of the AIS. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The progress of developing effective interventions against psychiatric disorders has been limited due to a lack of understanding of the underlying cellular and functional mechanisms. Recent research findings focused on exploring novel causes of psychiatric disorders have highlighted the importance of the axonal initial segment (AIS), a highly specialized neuronal structure critical for spike initiation of the action potential. In particular, the role of voltage-gated sodium channels, and their interactions with other protein partners in a tightly regulated macromolecular complex has been emphasized as a key component in the regulation of neuronal excitability. Deficits and excesses of excitability have been linked to the pathogenesis of brain disorders. Identification of the factors and regulatory pathways involved in proper AIS function, or its disruption, can lead to the development of novel interventions that target these mechanistic interactions, increasing treatment efficacy while reducing deleterious off-target effects for psychiatric disorders.
    Full-text · Article · Aug 2014 · Frontiers in Psychiatry
  • Source
    • "een gephyrin and PSD - 95 for binding to the intracellular tail of Nlgs , regulated by ligand binding and the phosphorylation level . A similar pY switch was previously proposed for the competitive binding of talin and tensin to the C - terminal tail of integrins ( Legate and Fä ssler , 2009 ) , and binding of ankyrin to the adhesion molecule L1 ( Gil et al . , 2003 ) . Because the distance between the gephyrin - binding sequence and the C - terminal PSD - 95 binding motif is relatively short ( 43 aa ) , and both gephyrin and PSD - 95 can form multimers ( Schlü ter et al . , 2006 ; Saiyed et al . , 2007 ) , a steric hindrance or binding motif sequestering could explain the competitive binding betwe"
    [Show abstract] [Hide abstract]
    ABSTRACT: Adhesion between neurexin-1β (Nrx1β) and neuroligin-1 (Nlg1) induces early recruitment of the postsynaptic density protein 95 (PSD-95) scaffold; however, the associated signaling mechanisms are unknown. To dissociate the effects of ligand binding and receptor multimerization, we compared conditions in which Nlg1 in neurons was bound to Nrx1β or nonactivating HA antibodies. Time-lapse imaging, fluorescence recovery after photobleaching, and single-particle tracking demonstrated that in addition to aggregating Nlg1, Nrx1β binding stimulates the interaction between Nlg1 and PSD-95. Phosphotyrosine immunoblots and pull-down of gephyrin by Nlg1 peptides in vitro showed that Nlg1 can be phosphorylated at a unique tyrosine (Y782), preventing gephyrin binding. Expression of Nlg1 point mutants in neurons indicated that Y782 phosphorylation controls the preferential binding of Nlg1 to PSD-95 versus gephyrin, and accordingly the formation of inhibitory and excitatory synapses. We propose that ligand-induced changes in the Nlg1 phosphotyrosine level control the balance between excitatory and inhibitory scaffold assembly during synapse formation and stabilization.
    Full-text · Article · Jun 2013 · Cell Reports
  • Source
    • "Some insight into the mechanism of ethanol action in cortical axons may be provided by our data, which show that neurons growing on an L1CAM substrate are resistant to ethanolmediated silencing of growth cone responses to guidance cues. L1CAM is highly abundant and natively distributed in both raft and non-raft domains (Kamiguchi et al, 2000; IC and DLB, unpublished observations), and can be stably anchored to actin via ankyrin (Bennett and Lambert, 1999; Gil et al, 2003). Such anchored transmembrane proteins have been proposed to stabilize and organize plasma membrane by generating compartment boundaries and by limiting protein and lipid diffusion (Kusumi et al, 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol exposure in utero is a common cause of mental retardation, but the targets and mechanisms of action are poorly understood. Several lines of data point toward alterations in cortical connectivity, suggesting that axon guidance may be vulnerable to alcohol exposure. To test this, we asked whether ethanol directly affects cortical axonal growth cone responses to guidance cues. We find that even low concentrations of ethanol (12.5 mM; 57.2 mg/dl) commonly observed in social drinking prevent growth cone responses to three mechanistically independent guidance cues, Semaphorin3A, Lysophosphatidic Acid, and Netrin-1. However, this effect is highly dependent on substrate; axonal growth cones extending on an L1 cell adhesion molecule (L1CAM) substrate retain responsiveness to cues following exposure to ethanol, while those growing on poly-L-lysine or N-cadherin do not. The effects of ethanol on axon extension are, by contrast, quite modest. Quantitative assessments of the effects of ethanol on the surface distribution of L1CAM in growth cones suggest that L1CAM homophilic interactions may be particularly relevant for retaining growth cone responsiveness following ethanol exposure. Together, our findings indicate that ethanol can directly and generally alter growth cone responses to guidance cues, that a substrate of L1CAM effectively antagonizes this effect, and that cortical axonal growth cone vulnerability to ethanol may be predicted in part based on the environment through which they are extending.
    Full-text · Article · Feb 2011 · Neuroscience
Show more