The L1 family of cell adhesion molecules (L1CAMs) are a subfamily of the immunoglobulin superfamily of transmembrane receptors, comprised of four structurally related proteins: L1, Close Homolog of L1 (CHL1), NrCAM, and Neurofascin. These CAMs contain six Ig like domains, five or six fibronectin like repeats, a transmembrane region and a cytoplasmic domain. The L1CAM family has been implicated in processes integral to nervous system development, including neurite outgrowth, neurite fasciculation and inter neuronal adhesion. L1CAM members are predominately expressed by neuronal, as well as some nonneuronal cells, during development. Except CHL1 all the other members of L1 family contain an alternatively spliced 12-nclueotide exon, encoding the amino acid residues RSLE in the neuronal splice forms but missing in the non-neuronal cells. The extracellular regions of L1CAM members are divergent and differ in their abilities to interact with extracellular, heterophilic ligands. The L1 ligands include other Ig-domain CAMs (such as NCAM, TAG-1/axonin and F11), proteoglycans type molecules (neurocan), beta1 integrins, and extra cellular matrix protein laminin, Neuropilin-1, FGF and EGF receptors. Some of these L1-interacting proteins also bind to other L1CAM members. For example TAG-1/axonin interact with L1 and NrCAM; L1, neurofascin and CHL1 binds to contactin family members. The cytoplasmic domains of L1CAM members are most highly conserved. Nevertheless, they have different cytoplasmic binding partners, and even those with similar binding partners may be involved in different signaling complexes and mechanisms. The most conserved feature of L1CAMs is their ability to interact with the actin cytoskeletal adapter protein ankyrin. The cytoplasmic ankyrin-binding domain, exhibits the highest degree of amino acid conservation throughout the L1 family.
He Y, Jensen GJ, Bjorkman PJ.; ''Cryo-electron tomography of homophilic adhesion mediated by the neural cell adhesion molecule L1.''; PubMedEurope PMCScholia
Maness PF, Schachner M.; ''Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration.''; PubMedEurope PMCScholia
Tuvia S, Garver TD, Bennett V.; ''The phosphorylation state of the FIGQY tyrosine of neurofascin determines ankyrin-binding activity and patterns of cell segregation.''; PubMedEurope PMCScholia
Jacob J, Haspel J, Kane-Goldsmith N, Grumet M.; ''L1 mediated homophilic binding and neurite outgrowth are modulated by alternative splicing of exon 2.''; PubMedEurope PMCScholia
Kulahin N, Li S, Hinsby A, Kiselyov V, Berezin V, Bock E.; ''Fibronectin type III (FN3) modules of the neuronal cell adhesion molecule L1 interact directly with the fibroblast growth factor (FGF) receptor.''; PubMedEurope PMCScholia
Nagaraj K, Hortsch M.; ''Phosphorylation of L1-type cell-adhesion molecules--ankyrins away!''; PubMedEurope PMCScholia
Zhao X, Yip PM, Siu CH.; ''Identification of a homophilic binding site in immunoglobulin-like domain 2 of the cell adhesion molecule L1.''; PubMedEurope PMCScholia
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Herron LR, Hill M, Davey F, Gunn-Moore FJ.; ''The intracellular interactions of the L1 family of cell adhesion molecules.''; PubMedEurope PMCScholia
Schmid RS, Maness PF.; ''L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth.''; PubMedEurope PMCScholia
Nishimura T, Fukata Y, Kato K, Yamaguchi T, Matsuura Y, Kamiguchi H, Kaibuchi K.; ''CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth.''; PubMedEurope PMCScholia
Koroll M, Rathjen FG, Volkmer H.; ''The neural cell recognition molecule neurofascin interacts with syntenin-1 but not with syntenin-2, both of which reveal self-associating activity.''; PubMedEurope PMCScholia
Schaefer AW, Kamiguchi H, Wong EV, Beach CM, Landreth G, Lemmon V.; ''Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization.''; PubMedEurope PMCScholia
Wong EV, Schaefer AW, Landreth G, Lemmon V.; ''Casein kinase II phosphorylates the neural cell adhesion molecule L1.''; PubMedEurope PMCScholia
Kamiguchi H, Lemmon V.; ''Recycling of the cell adhesion molecule L1 in axonal growth cones.''; PubMedEurope PMCScholia
Whittard JD, Sakurai T, Cassella MR, Gazdoiu M, Felsenfeld DP.; ''MAP kinase pathway-dependent phosphorylation of the L1-CAM ankyrin binding site regulates neuronal growth.''; PubMedEurope PMCScholia
Zhang X, Davis JQ, Carpenter S, Bennett V.; ''Structural requirements for association of neurofascin with ankyrin.''; PubMedEurope PMCScholia
Peretti D, Peris L, Rosso S, Quiroga S, Cáceres A.; ''Evidence for the involvement of KIF4 in the anterograde transport of L1-containing vesicles.''; PubMedEurope PMCScholia
Islam R, Kristiansen LV, Romani S, Garcia-Alonso L, Hortsch M.; ''Activation of EGF receptor kinase by L1-mediated homophilic cell interactions.''; PubMedEurope PMCScholia
Tomatis VM, Trenchi A, Gomez GA, Daniotti JL.; ''Acyl-protein thioesterase 2 catalyzes the deacylation of peripheral membrane-associated GAP-43.''; PubMedEurope PMCScholia
Zhao X, Siu CH.; ''Colocalization of the homophilic binding site and the neuritogenic activity of the cell adhesion molecule L1 to its second Ig-like domain.''; PubMedEurope PMCScholia
Felding-Habermann B, Silletti S, Mei F, Siu CH, Yip PM, Brooks PC, Cheresh DA, O'Toole TE, Ginsberg MH, Montgomery AM.; ''A single immunoglobulin-like domain of the human neural cell adhesion molecule L1 supports adhesion by multiple vascular and platelet integrins.''; PubMedEurope PMCScholia
Kadmon G, Kowitz A, Altevogt P, Schachner M.; ''The neural cell adhesion molecule N-CAM enhances L1-dependent cell-cell interactions.''; PubMedEurope PMCScholia
Cheng L, Lemmon S, Lemmon V.; ''RanBPM is an L1-interacting protein that regulates L1-mediated mitogen-activated protein kinase activation.''; PubMedEurope PMCScholia
Gast D, Riedle S, Kiefel H, Müerköster SS, Schäfer H, Schäfer MK, Altevogt P.; ''The RGD integrin binding site in human L1-CAM is important for nuclear signaling.''; PubMedEurope PMCScholia
Kamiguchi H.; ''The mechanism of axon growth: what we have learned from the cell adhesion molecule L1.''; PubMedEurope PMCScholia
Volkmer H, Leuschner R, Zacharias U, Rathjen FG.; ''Neurofascin induces neurites by heterophilic interactions with axonal NrCAM while NrCAM requires F11 on the axonal surface to extend neurites.''; PubMedEurope PMCScholia
Kristiansen LV, Marques FA, Soroka V, Ronn LC, Kiselyov V, Pedersen N, Berezin V, Bock E.; ''Homophilic NCAM interactions interfere with L1 stimulated neurite outgrowth.''; PubMedEurope PMCScholia
Zheng CF, Guan KL.; ''Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.''; PubMedEurope PMCScholia
Castellani V, De Angelis E, Kenwrick S, Rougon G.; ''Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A.''; PubMedEurope PMCScholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMedEurope PMCScholia
Gauthier-Campbell C, Bredt DS, Murphy TH, El-Husseini Ael-D.; ''Regulation of dendritic branching and filopodia formation in hippocampal neurons by specific acylated protein motifs.''; PubMedEurope PMCScholia
Kamiguchi H, Long KE, Pendergast M, Schaefer AW, Rapoport I, Kirchhausen T, Lemmon V.; ''The neural cell adhesion molecule L1 interacts with the AP-2 adaptor and is endocytosed via the clathrin-mediated pathway.''; PubMedEurope PMCScholia
Panicker AK, Buhusi M, Erickson A, Maness PF.; ''Endocytosis of beta1 integrins is an early event in migration promoted by the cell adhesion molecule L1.''; PubMedEurope PMCScholia
Needham LK, Thelen K, Maness PF.; ''Cytoplasmic domain mutations of the L1 cell adhesion molecule reduce L1-ankyrin interactions.''; PubMedEurope PMCScholia
Nishimura K, Akiyama H, Komada M, Kamiguchi H.; ''betaIV-spectrin forms a diffusion barrier against L1CAM at the axon initial segment.''; PubMedEurope PMCScholia
Sakurai T, Gil OD, Whittard JD, Gazdoiu M, Joseph T, Wu J, Waksman A, Benson DL, Salton SR, Felsenfeld DP.; ''Interactions between the L1 cell adhesion molecule and ezrin support traction-force generation and can be regulated by tyrosine phosphorylation.''; PubMedEurope PMCScholia
Nakata A, Kamiguchi H.; ''Serine phosphorylation by casein kinase II controls endocytic L1 trafficking and axon growth.''; PubMedEurope PMCScholia
Schaefer AW, Kamei Y, Kamiguchi H, Wong EV, Rapoport I, Kirchhausen T, Beach CM, Landreth G, Lemmon SK, Lemmon V.; ''L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1.''; PubMedEurope PMCScholia
Grumet M, Edelman GM.; ''Neuron-glia cell adhesion molecule interacts with neurons and astroglia via different binding mechanisms.''; PubMedEurope PMCScholia
Horstkorte R, Schachner M, Magyar JP, Vorherr T, Schmitz B.; ''The fourth immunoglobulin-like domain of NCAM contains a carbohydrate recognition domain for oligomannosidic glycans implicated in association with L1 and neurite outgrowth.''; PubMedEurope PMCScholia
L1-L1 trans-homodimers interact with the fibroblast growth factor receptor (FGFR). The CAM homology domain (CHD) in the FGFR, which resides between Ig like domains 1 and 2, interacts with the putative FGFR-CHD binding motif in the Fn3 module 4 of L1. This interaction leads to activation of the tyrosine kinase domain of the FGFR and subsequent activation of PLCgamma. PLCgamma then hydrolyses PIP2 to generate IP3 and DAG which finally leads to an increase in localized Ca+2 influx and activation of Ca+2/Calmodulin kinase II.
L1 cross linking can activate MAPK cascade components MEK1/2, ERK1/2, as well as Src, Raf-1,and p90rsk. MAP kinase signaling requires endocytosis mediated by Src. ERK2 can phos-phorylate internalized L1 at serine residues 1204 and 1248. This phosphorylation may increase the neurite growth.
Membrane bound L1 is internalized through clathrin coated vesicles and is endocytosed into recycling endosomes. Moreover, L1 promotes co-endocytosis of beta1 integrins with which it is associated into early endosomes.
L1 translocated to the non raft membranes of the C-domain is dephosphorylated. A number of potential candidate phosphatases exist including phosphotyrosine phosphatases. Dephosphorylation of Y1176 allows L1 binding to AP-2, an adaptor required for clathrin mediated internalization of L1.
While HNK-1 (human natural killer 1) carbohydrate is expressed on several kinds of cell adhesion molecules in the nervous system, L1CAM is the major carrier of HNK-1 carbohydrate. HNK-1 also functions as a ligand for Laminin. L1 binds in a concentration-dependent and saturating manner to Laminin in presence of HNK-1.
L1 in the C-domain membrane is internalized via clathrin mediated endocytosis. The assembly of clathrin coats at the plasma membrane depends on the adaptor complex AP-2 which is composed of two large chains (alpha and beta1 or beta2 adaptin), one medium (mu2) chain, and one small chain (sigma2). When dephosphorylated, the sorting signal/endocytic motif YRSLE sequence enables L1 to directly bind the mu2 subunit of AP-2, and concentrates L1 molecules in clathrin coated areas of the plasma membrane.
DM GRASP/ALCAM/BEN is one of the heterodimerizing partners for L1/NgCAM. Interation between L1/NgCAM and DM GRASP in the growth cone membrane is involved in L1 stimulated neurite outgrowth. Trans binding of L1 on retinal growth cones to ALCAM on the superior colliculus potentiates adhesion, leading to correct synaptic targeting.
Endocytosis is followed by the vesicular transport and recycling of L1 from central (C)-domain into the peripheral (P)-domain of growth cones. Microtubules serve as a rail on which motor proteins convey L1 containing organelles. KIF4 is a plus end motor protein involved in the anterograde transport of L1 containing vesicles along microtubules.
Syntenin-1 is an intracellular binding partner of neurofascin. Syntenin-1 contains two PDZ domains; the second one is a binding site for the COOH terminus of neurofascin.
L1 recruits membrane skeletal component ankyrin to cell to cell contact sites in response to cis interaction with homophilic axonin 1/TAG 1 or trans L1 L1 homophilic interaction although in mammalian cells trans binding interactions are not required. L1 interacts with ankyrin proteins through two highly conserved amino acid sequence motifs, LADY and FIGQY. Ankyrin binding immobilizes L1 molecules in the neuronal plasma membrane. This interaction is required for axon maintenance. L1 also elevates cyclic AMP levels in neurons via ankyrin B and mediates Ca+2 dependent attraction.The L1/ankyrin interaction is a vital determinant of synaptic targeting of retinal axons to the superior colliculus and cooperates with EphrinB/EphB signaling to induce axon branch attraction.
Ankyrins are bifunctional linker proteins that tether L1 to the membrane associated, spectrin based actin cytoskeleton. Spectrin is a tetramer of two alpha- and two beta-chains. The spectrin alpha chain has 21 and the beta chain has 16 (conventional beta) or 30 (heavy beta) successive triple helix repeats. At the N-terminus of beta spectrin, there is a pair of CH (calponin homology) domains which together form an actin binding domain, while the triple helical repeats 14-15 bind ankyrin. Interaction with spectrin bound F-actin blocks the mobility of L1 and this immobilization mediates adjacent neuron adhesions.
L1 can function as a trans-heterophilic ligand for multiple members of the integrin superfamily. It binds multiple integrins including alphavbeta3, alphavbeta1, alpha5beta1, alphaIIbbeta3 and alpha9beta 1. The RGD motif in the sixth Ig domain and the third FnIII repeat of L1 are important for these interactions, which serves to strengthen the adhesion of the neuron to the extracellular matrix. L1 and beta1 integrins association activates a common intracellular signaling pathway. This pathway involves the sequential activation of the tyrosine kinase c-Src, PI3 kinase, Vav2 guanine nucleotide exchange factor, Rac1 GTPase, PAK1, MEK, and the MAP kinases ERK1/2, which is essential for L1 induced neurite outgrowth and cell motility.
Doublecortin is a microtubule associated protein expressed in neurons. Mutated doublecortin has been linked to the neuronal migration disorder X linked subcortical laminar heterotopia (double cortex)/lissencephaly. It binds neurofascin when the FIGQY motif of the latter protein is phosphorylated.
Shootin-1 acts as a linker protein, binding L1 to moving actin filaments in axonal growth cones. This interaction mediates the migration of L1 on the plasma membrane from P-domain to the C-domain of the growth cone and enhances neurite elongation.
The small GTPase p21Rac1 is one of the important targets of VAV2 GEF activity. On L1 stimulation tyrosine phosphorylated VAV2, catalyses GDP/GTP exchange on Rac1.
EPH kinase Cek5/EPHB2 phosphorylates tyrosine residue in the cytoplasmic domain of NgCAM/L1. The tyrosine 1229 may be the target site. EphrinB/EphB signaling enhances L1-dependent adhesion to substrates including ALCAM and extracellular matrix proteins.
L1CAM and EGFR engage in a weak heterophilic trans interaction and this induces EGFR tyrosine kinase activity and its activation. However, this trans interaction alone is not sufficient to induce EGFR autophosphorylation, which requires additional cis type interactions between the two proteins.
The highly conserved FIGQY motif in the cytoplasmic domain of neurofascin is phosphorylated by tyrosine kinases in response to external signals. Phosphorylation of the tyrosine in the FIGQY motif inhibits ankyrin binding.
Axonin-1 expressed on the commissural axons interacts in trans with NrCAM expressed on floor plate. This interaction is required for commissural axons to enter the floor plate and cross the midline.
Interaction with ERM may lead to lateral oligomerization of phosphorylated L1 and this enhances the homophilic trans adhesion of L1. L1 mediates cell-cell adhesion by a trans-homophilic binding mechanism. In the nonengaged resting state the L1 N-terminal Ig domains adopt a horseshoe like structure due to an intramolecular binding between domains 1 and 4 or 2 and 3, respectively. When engaged in homophilic binding between adjacent cells, L1 could undergo a conformational change leading to a pairwise antiparallel alignment of Ig domains 1-4 and 2-3.
L1 and RanBPM interact with one another and the N-terminus of RanBPM was sufficient for the interaction with L1. RanBPM interacts with RAN, a Ras-like small GTPase that functions as a carrier in nuclear-cytoplasmic exchange. It directly interacts with Sos to activate Ras and induce ERK phosphorylation. RanBPM might function as an adaptor to mediate L1-induced ERK activation.
NrCAM is the only mammalian L1CAM family member containing a consensus PDZ binding motif. NrCAM interacts with the PDZ domain containing proteins SAP-102, SAP-95 and SAP-97 and recruits them to the cell membrane. These SAP family members are colocalized with NrCAM in photoreceptor cells of the mammalian retina.
Binding of ankyrins is dependent on the phosphorylation and dephosphorylation state of the tyrosine in the L1 FIGQY motif. In the dephosphorylated state ankyrins bind to L1 and in the phosphorylated state L1 releases from ankyrins and binds to doublecortin. The specific kinase that is responsible for the phosphorylation of this tyrosine residue is still unknown, but components of the MAP kinase pathway may regulate this event. Tyrosine phosphorylation abolishes ankyrin binding and also increases L1 lateral mobility and neurite growth
L1 and NCAM1 co-expressed on a single cell interact with each other via the fourth Ig domain of NCAM1 and the oligomannose type oligosaccharides carried by L1. This interaction has synergetic effects on L1-mediated cell aggregation and adhesion, a phenomenon referred to as 'assisted homophilic L1-L1 trans-binding'.
L1 crosslinking leads to the tyrosine phosphorylation and activation of VAV2. Tyr-172 in VAV2 binds to the DBL homology region autoinhibiting its GEF-activity. Tyrosine kinase src may phosphorylate this residue and relieve the autoinhibition.
p90rsk associates with the internalized L1 in the endosomes and phosphorylates it at Ser1152. This phosphorylation may regulate the interactions of L1 and intracellular signaling cascades or cytoskeletal elements involved in neurite outgrowth on specific substrates.
The COOH termini of all ERM proteins have sequence motifs that bind directly to F-actin. The L1 molecules on the cell surface are translocated to the C-domain by coupling with the retrograde F-actin. The force generated by linking L1 clusters with retrograde F-actin flow leads to the migration of the growth cone.
L1 interacts with neuropilin 1 (NP-1) through a conserved sequence (FASNKL) present with in the Ig1 domain of L1 and this association is required as a part of semaphorin 3A (Sema3A) receptor complex for axon guidance responses. L1 interacts with NP-1 in cis to form a receptor complex that induces repulsive turning of the growth cone in response to Sema3A binding, whereas trans interaction of L1 with NP-1 switches Sema3A triggered repulsion to attraction.
By analogy to the well-studied chicken system, L1 can be coexpressed with axonin-1 (TAG-1/Contactin-2) on same growth cone membrane and the two proteins form a cis-heterodimer required for neurite growth.
NrCAM is expressed specifically at node of ranvier where it interacts with the cytoskeletal adaptor protein ankyrin-G with the conserved motif F1272IGQY.
By analogy to the well-studied chicken system, L1 heterophilically binds to F3/F11/Contactin-1 in cis manner via an L1-binding site resides in the first two immunoglobulin-like domains of Contactin-1.
Heat-stable antigen (HSA/mouse CD24) is expressed in both haematopoietic and neural cells. HSA binds to L1CAM and mediate cell adhesion and intracellular Ca2+ signals in neurons and B lymphoblasts.
The cytoplasmic domains of neurofascin contains a highly conserved sequence (F1315IGQY) that binds ankyrin. The membrane binding domain of ankyrin has two distinct binding sites for neurofascin and is proposed to form lateral complexes between ion channels and cell adhesion molecules as well as to couple these proteins to the spectrin based membrane skeleton.
Numb is thought to be a phosphotyrosine binding (PTB) domain containing cargo specific adaptor protein, which links specific cargo to the endocytic machinery. It associates with collapsin response mediator protein-2 (CRMP 2) with its PTB domain and alpha adaptin (a subunit of the AP 2 adaptor complex) through its tripeptide Asp-Pro-Phe (DPF) motif, and is involved in clathrin dependent endocytosis at the plasma membrane. Numb is associated with L1 under physiological conditions and functions in endocytosis of L1 in the C domain membrane of axonal growth cones.
Dynamin is a neuronal phosphoprotein and a GTPase enzyme which mediates late stages of endocytosis in both neural and non-neural cells. Dynamin is involved in the membrane fusion event that results in the formation of clathrin-coated vesicles.
CHL1 binds the Sema3A receptor, Neuropilin-1 (NP-1), via a conserved sequence in the Ig1 domain, and acts as obligate coreceptor to mediate Sema3A-induced growth cone collapse and axon repulsion.
Ankyrins link both L1 and ion channel proteins, coupling them to the spectrin actin cytoskeleton. In the nervous system ankyrins interact with voltage gated channels and cluster them in axon initial segments to generate action potentials. At these points the actin spectrin network is linked via ankyrins to voltage gated sodium channels, L1, and the voltage gated potassium ion channel subunits, KCNQ2 and KCNQ3.
CHL1 interacts with alpha1beta1/alpha2beta1 integrins in cis on the cell surface and promotes intracellular signaling, which stimulates cell migration on extracellular matrix proteins such as collagen-I. The integrin interaction motif, DGEA in the Ig6 domain of CHL1, is necessary to potentiate migration to collagen-I. CHL1 interacts with integrins to mediate radial migration of neural precursors in the development neocortex, and suppresses neuronal branching during migration.
In its bound state PAK dimers are arranged in head-to-tail fashion and are maintained in inactive conformation in which the catalytic domain binds the kinase inhibitory (KI) domain. All PAK family members are direct effectors of Rac1. Rac1 binds to a conserved Cdc42/Rac interactive binding (CRIB) domain in PAK1. This binding stimulates serine/threonine kinase activity of PAK1 by a mechanism involving autophosphorylation. Phosphorylation of S-144 and T-423 are required for the activation of PAK1. This phosphorylation disables the KI-domain-kinase interaction and thereby reduces the affinity of the PAK dimers. Its been demonstarted that L1 stimulation propagates through VAV2-Rac1-Pak1 to MEK-ERK. It has been shown that Pak1 is able to phosphoarylate T292 and S298 on MEK, which is essential for the functional association of MEK with Raf.
Close homolog of L1 (CHL1), associates with Contactin-6/NB-3, a member of the F3/contactin family of neural recognition molecules, and enhances its cell surface expression. CHL1 and NB3 may engage in a cis-interaction and form a coreceptor/adhesion complex on the neuronal surface. CHL1/NB3 clustering activates protein tyrosine phosphatase alpha (PTP alpha), which dephosphorylates and activates Fyn. Both PTP alpha and Fyn are required for proper apical dendrite orientation of deep layer pyramidal neurons.
CKII phosphorylates L1CAM at serine 1181, just after the AP-2 recognition site (Y1176RSLE motif). CKII-dependent phosphorylation of S1181 has been shown to regulate trafficking of the internalized L1 and subsequent axon growth.
L1CAM binds with high affinity to the proteoglycan neurocan. Neurocan binds to the first Ig domain of L1CAM through its sushi module and a chondroitin sulphate chain. This interaction interferes with the homophilic interaction of L1CAM and inhibits neuronal adhesion and neurite extension mediated by L1CAM.
CHL1 associates with the sub-membranous actin cytoskeleton through a motif for binding the spectrin adaptor protein ankyrin in the cytoplasmic domain (F1181IGAY), which is somewhat different from L1 (F1224IGQY).
The tyrosine based sorting motif (YRSLE) in L1CD is required for clathrin mediated endocytosis. Y1176 of the YRSLE motif is phosphorylated by SRC tyrosine kinase associated with lipid rafts in the P-domain of the growth cone. Phosphorylation of Y1176 prevents L1 binding to AP-2, an adaptor required for clathrin mediated internalization of L1.
Neurofascin, expressed at the paranodal loop might be the glial receptor for the paranodin/Caspr-contactin complex. Neurofascin-Caspr-contactin complex forms the core structure of paranodal junctions.
CHL1 accumulates in the presynaptic plasma membrane and it recruits heat shock cognate 71 kDa protein (HSP7C/HSC70), in an ADP dependent manner. HSC70 interacts with the intracellular domain of CHL1. Upon synapse activation, CHL1 along with HSC70 is endocytosed and is targeted to synaptic vesicles (SVs). In synapses, HSC70 regulates uncoating of synaptic vesicles (SVs) in the clathrin-dependent recycling pathway (Leshchyns'ka et al. 2006, Zinsmaier & Bronk 2001).
Ezrin Radixin Moesin (ERM) are the members of the FERM domain (F for Band 4.1 protein, E for ezrin, R for radixin and M for moesin) containing proteins involved in localizing proteins to the plasma membrane. L1 is coupled to the tread milling actin cytoskeleton through interaction with ERM proteins. The motif KxxKYxV in the juxtamembrane region and the YRSLE sequence in L1CD are important for the ERM binding. This interaction provides a link between L1 and the actin cytoskeleton and plays a critical role in the traction force generation and regulation of neurite branching.
L1CAM members are predominately expressed by neuronal, as well as some nonneuronal cells, during development. Except CHL1 all the other members of L1 family contain an alternatively spliced 12-nclueotide exon, encoding the amino acid residues RSLE in the neuronal splice forms but missing in the non-neuronal cells. The extracellular regions of L1CAM members are divergent and differ in their abilities to interact with extracellular, heterophilic ligands. The L1 ligands include other Ig-domain CAMs (such as NCAM, TAG-1/axonin and F11), proteoglycans type molecules (neurocan), beta1 integrins, and extra cellular matrix protein laminin, Neuropilin-1, FGF and EGF receptors. Some of these L1-interacting proteins also bind to other L1CAM members. For example TAG-1/axonin interact with L1 and NrCAM; L1, neurofascin and CHL1 binds to contactin family members. The cytoplasmic domains of L1CAM members are most highly conserved. Nevertheless, they have different cytoplasmic binding partners, and even those with similar binding partners may be involved in different signaling complexes and mechanisms. The most conserved feature of L1CAMs is their ability to interact with the actin cytoskeletal adapter protein ankyrin. The cytoplasmic ankyrin-binding domain, exhibits the highest degree of amino acid conservation throughout the L1 family.
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DataNodes
L1 KIF4
microtubuleNUMB
alpha adaptinNUMB CRMP-2
alpha-adaptinAnkyrin Spectrin
F-actinCNTN1
CASPR complexNrCAM Ankyrin spectrin based actin
Na+/K+ channelNrCAM Ankyrin
spectrin based actinERM
F-actinShootin-1
F-actinAnnotated Interactions
NUMB
alpha adaptinNrCAM Ankyrin
spectrin based actinMicrotubules serve as a rail on which motor proteins convey L1 containing organelles. KIF4 is a plus end motor protein involved in the anterograde transport of L1 containing vesicles along microtubules.
Ankyrin binding immobilizes L1 molecules in the neuronal plasma membrane. This interaction is required for axon maintenance. L1 also elevates cyclic AMP levels in neurons via ankyrin B and mediates Ca+2 dependent attraction.The L1/ankyrin interaction is a vital determinant of synaptic targeting of retinal axons to the superior colliculus and cooperates with EphrinB/EphB signaling to induce axon branch attraction.
Interaction with spectrin bound F-actin blocks the mobility of L1 and this immobilization mediates adjacent neuron adhesions.
L1 and beta1 integrins association activates a common intracellular signaling pathway. This pathway involves the sequential activation of the tyrosine kinase c-Src, PI3 kinase, Vav2 guanine nucleotide exchange factor, Rac1 GTPase, PAK1, MEK, and the MAP kinases ERK1/2, which is essential for L1 induced neurite outgrowth and cell motility.
L1 mediates cell-cell adhesion by a trans-homophilic binding mechanism. In the nonengaged resting state the L1 N-terminal Ig domains adopt a horseshoe like structure due to an intramolecular binding between domains 1 and 4 or 2 and 3, respectively. When engaged in homophilic binding between adjacent cells, L1 could undergo a conformational change leading to a pairwise antiparallel alignment of Ig domains 1-4 and 2-3.
The specific kinase that is responsible for the phosphorylation of this tyrosine residue is still unknown, but components of the MAP kinase pathway may regulate this event. Tyrosine phosphorylation abolishes ankyrin binding and also increases L1 lateral mobility and neurite growth
L1 interacts with NP-1 in cis to form a receptor complex that induces repulsive turning of the growth cone in response to Sema3A binding, whereas trans interaction of L1 with NP-1 switches Sema3A triggered repulsion to attraction.
All PAK family members are direct effectors of Rac1. Rac1 binds to a conserved Cdc42/Rac interactive binding (CRIB) domain in PAK1. This binding stimulates serine/threonine kinase activity of PAK1 by a mechanism involving autophosphorylation. Phosphorylation of S-144 and T-423 are required for the activation of PAK1. This phosphorylation disables the KI-domain-kinase interaction and thereby reduces the affinity of the PAK dimers.
Its been demonstarted that L1 stimulation propagates through VAV2-Rac1-Pak1 to MEK-ERK. It has been shown that Pak1 is able to phosphoarylate T292 and S298 on MEK, which is essential for the functional association of MEK with Raf.
CHL1/NB3 clustering activates protein tyrosine phosphatase alpha (PTP alpha), which dephosphorylates and activates Fyn. Both PTP alpha and Fyn are required for proper apical dendrite orientation of deep layer pyramidal neurons.