Close Homolog of L1 Is an Enhancer of Integrin-mediated Cell Migration

Abstract

Close homolog of L1 (CHL1) is a member of the L1 family of cell adhesion molecules expressed by subpopulations of neurons and glia in the central and peripheral nervous system. It promotes neurite outgrowth and neuronal survival in vitro. This study describes a novel function for CHL1 in potentiating integrin-dependent cell migration toward extracellular matrix proteins. Expression of CHL1 in HEK293 cells stimulated their haptotactic migration toward collagen I, fibronectin, laminin, and vitronectin substrates in Transwell assays. CHL1-potentiated cell migration to collagen I was dependent on ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins, as shown with function blocking antibodies. Potentiated migration relied on the early integrin signaling intermediates c-Src, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase. Enhancement of migration was disrupted by mutation of a potential integrin interaction motif Asp-Gly-Glu-Ala (DGEA) in the sixth immunoglobulin domain of CHL1, suggesting that CHL1 functionally interacts with ␤ 1 integrins through this domain. CHL1 was shown to associate with ␤ 1 integrins on the cell surface by antibody-induced co-capping. Through a cytoplasmic domain sequence containing a conserved tyrosine residue (Phe-Ile-Gly-Ala-Tyr), CHL1 recruited the actin cytoskeletal adapter protein ankyrin to the plasma membrane, and this sequence was necessary for promoting integrin-dependent migration to extracellular matrix proteins. These results support a role for CHL1 in integrin-dependent cell migration that may be physiologically important in regulating cell migration in nerve regeneration and cortical development.

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

“…CHL1 functions coordinately with β1-integrins during the migration process, since haptotactic migration of embryonic cortical neurons is inhibited in the presence of integrin blocking antibodies in vitro. Cell-based assays implicate c-Src, PI3 kinase, and ERK1/2 in the CHL1-integrin signaling pathway [12]. Integrins have been shown to participate in the mechanism of radial migration of embryonic cortical neurons [13] but appear to function when expressed on radial glia, rather than on neurons [14].…”

Lipid Raft-dependent Endocytosis of Close Homolog of Adhesion Molecule L1 (CHL1) Promotes Neuritogenesis

“…The initial focus was centered on ankyrin-B, because ankyrins are binding partners for CHL1 (3). Based on the observations that ankyrins interact with spectrins (30) and that ␤II spectrin accumulates in axons, where CHL1 also accumulates (14), the levels of ␤II spectrin in lipid rafts were also analyzed.…”

“…The close homolog of L1 (CHL1) 3 is a cell adhesion molecule that belongs to the immunoglobulin superfamily due to the presence of six Ig-like domains in its extracellular part. CHL1 is highly expressed in neurons but is also detectable in astrocytes, oligodendrocytes, and Schwann cells (1).…”

“…CHL1 interacts with and recruits to the cell surface plasma membrane the cytoskeleton-linker proteins such as ankyrin and the ezrin-radixin-moesin (ERM) family of proteins (3,12). Mutations in the ankyrin-and ERM-binding motifs abrogate the ability of CHL1 to promote neuronal migration and neurite outgrowth (3,12). How the association of CHL1 with the cytoskeleton is regulated remains poorly understood.…”

Glial Scar Expression of CHL1, the Close Homolog of the Adhesion Molecule L1, Limits Recovery after Spinal Cord Injury

“…Among the recognition molecules of the Ig superfamily, the close homolog of L1 (CHL1) was discovered as a novel member of the L1 family (Holm et al, 1996;Hillenbrand et al, 1999). Like L1, CHL1 promotes neurite outgrowth and neuronal survival, when substratecoated in vitro (Chen et al, 1999) and, as a coreceptor with integrins, enhances cell migration (Holm et al, 1996;Hillenbrand et al, 1999;Buhusi et al, 2003).…”