L1CAM interactions (Homo sapiens)
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Description
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. View original pathway at Reactome.
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. View original pathway at Reactome.
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alpha1beta1, alpha2beta1,
alpha10beta1(S1204,
1248):ERK2:clathrin-dynamin complexAnnotated Interactions
alpha1beta1, alpha2beta1,
alpha10beta1MAP2K1 activation requires the phosphorylation of two serine residues (S218 and S222) in the activation loop.
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.
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.
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 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.
Interaction with spectrin bound F-actin blocks the mobility of L1 and this immobilization mediates adjacent neuron adhesions.
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.
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.
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
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.
(S1204,
1248):ERK2:clathrin-dynamin complex