The Neural Cell Adhesion Molecule L1 Potentiates Integrin-Dependent Cell Migration to Extracellular Matrix Proteins

Abstract

The L1 adhesion molecule regulates axon growth and is mutated in the X-linked mental retardation syndrome CRASH (acronym for corpus callosum agenesis, retardation, aphasia, spastic paraplegia, hydrocephalus). A novel role for L1 as a potentiator of neuronal cell migration to extracellular matrix proteins through beta1 integrins and intracellular signaling to mitogen-activated protein (MAP) kinase was identified. L1 potentiated haptotactic migration of B35 neuroblastoma cells toward fibronectin, vitronectin, and laminin through the signaling intermediates c-Src, phosphatidylinositol-3 kinase, and MAP kinase. L1 potentiated migration toward fibronectin through alpha5beta1 integrin in human embryonic kidney 293 cells and depended on determinants of L1 endocytosis: dynamin I, c-Src, and the AP2/clathrin binding site (Arg-Ser-Leu-Glu) in the neuronal splice form of L1. L1 clustering on the cell surface enhanced the internalization of activated beta1 integrins and L1 into distinct endocytic vesicles. L1-potentiated migration, enhancement of beta1 integrin endocytosis, and activation of MAP kinase were coordinately inhibited by mutation of an RGD sequence in the sixth immunoglobulin-like domain of L1. Moreover, three CRASH mutations in the L1 cytoplasmic domain (1194L, S1224L, Y1229H), two of which interfere with ankyrin association, inhibited L1-potentiated migration and MAP kinase activation. Function-blocking antibodies to L1 and beta1 integrin retarded the migration of 5-bromo-2'-deoxyuridine-labeled mouse cerebellar granule cells in slice cultures, underscoring the potential physiological relevance of these findings. These studies suggest that L1 functionally interacts with beta1 integrins to potentiate neuronal migration toward extracellular matrix proteins through endocytosis and MAP kinase signaling, and that impairment of this function by L1 cytoplasmic domain mutations may contribute to neurological deficits in CRASH.

L1 augments cell migration and tumor growth but not β3 integrin expression in ovarian carcinomas

“…[7][8][9] In transfected cell lines or in carcinoma cells selected for high or low expression, L1 was able to modulate the haptotactic cell migration on various extracellular matrix proteins. 17 These results were confirmed using neuroblastoma cells, 34 as well as in fibroblasts and melanoma cells expressing L1. 24 In our study we used overexpression in ovarian carcinoma cell lines to demonstrate a similar role for L1 in this tumor.…”

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…L1 promotes cell-matrix adhesion and migration of tumor cells on ECM proteins, such as fibronectin and laminin, by associating with integrins through an integrin recognition motif. Namely, integrins a v b 5 , a v b 3 and a 5 b 1 have been found to associate with L1 [49,[60][61][62]. In these studies, integrin-mediated signaling events induced by associated L1 seem to be responsible for promoted cell migration.…”

L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth

“…The interaction is mediated by a conserved RGD binding motif in the sixth immunoglobin-like domain and the third fibronectin type III repeat of L1 [2,3], which serves to strengthen adhesion of the cell to the ECM (Fig. 1).…”