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      Plasmin-Sensitive Dibasic Sequences in the Third Fibronectin-like Domain of L1–Cell Adhesion Molecule (Cam) Facilitate Homomultimerization and Concomitant Integrin Recruitment

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          Abstract

          L1 is a multidomain transmembrane neural recognition molecule essential for neurohistogenesis. While moieties in the immunoglobulin-like domains of L1 have been implicated in both heterophilic and homophilic binding, the function of the fibronectin (FN)-like repeats remains largely unresolved. Here, we demonstrate that the third FN-like repeat of L1 (FN3) spontaneously homomultimerizes to form trimeric and higher order complexes. Remarkably, these complexes support direct RGD-independent interactions with several integrins, including α vβ 3 and α 5β 1. A pep- tide derived from the putative C-C′ loop of FN3 (GSQRKHSKRHIHKDHV 852) also forms trimeric complexes and supports α vβ 3 and α 5β 1 binding. Substitution of the dibasic RK 841 and KR 845 sequences within this peptide or the FN3 domain limited multimerization and abrogated integrin binding. Evidence is presented that the multimerization of, and integrin binding to, the FN3 domain is regulated both by conformational constraints imposed by other domains and by plasmin- mediated cleavage within the sequence RK HSK RH 846. The integrin α 9β 1, which also recognizes the FN3 domain, colocalizes with L1 in a manner restricted to sites of cell–cell contact. We propose that distal receptor ligation events at the cell–cell interface may induce a conformational change within the L1 ectodomain that culminates in receptor multimerization and integrin recruitment via interaction with the FN3 domain.

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          Most cited references 71

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          Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.

          VPF/VEGF is a multifunctional cytokine that contributes to angiogenesis by both direct and indirect mechanisms. On the one hand, VPF/VEGF stimulates the ECs lining nearby microvessels to proliferate, to migrate, and to alter their pattern of gene expression. On the other hand, VPF/VEGF renders these same microvascular ECs hyperpermeable so that they spill plasma proteins into the extravascular space, leading to the clotting of extravasated fibrinogen with deposition of a fibrin gel. Extravascular fibrin serves as a provisional matrix that favors and supports the ingrowth of new blood vessels and other mesenchymal cells that generate mature, vascularized stroma. These same principles apply in tumors, in several examples of non-neoplastic pathology, and in physiological processes that involve angiogenesis and new stroma generation. In all of these examples, microvascular hyperpermeability and the introduction of a provisional, plasma-derived matrix precede and accompany the onset of EC division and new blood vessel formation. It would seem, therefore, that tumors have "borrowed" fundamental mechanisms that developed in multicellular organisms for purposes of tissue defense, renewal, and repair. VPF/VEGF, therefore has taught us something new about angiogenesis; namely, that vascular hyperpermeability and consequent plasma protein extravasation are important, perhaps essential, elements in its generation. However, this finding raises a paradox. While VPF/VEGF induces vascular hyperpermeability, other potent angiogenic factors apparently do not, at least in subtoxic concentrations that are more than sufficient to induce angiogenesis. Nonetheless, wherever angiogenesis has been studied, the newly generated vessels have been found to be hyperpermeable. How, therefore, do angiogenic factors other than VPF/VEGF lead to the formation of new and leaky blood vessels? We do not as yet have a complete answer to this question. One possibility is that at least some angiogenic factors mediate their effect by inducing or stimulating the expression of VPF/VEGF. In fact, there is already one clear example of this. TGF-alpha is a potent angiogenic factor but does not itself increase microvascular permeability. However, TGF-alpha strikingly upregulates VPF/VEGF expression in cultured keratinocytes and is thought to be responsible, at least in part, for the overexpression of VPF/VEGF in psoriasis. Moreover, overexpression of TGF-alpha, along with that of the EGF receptor with which it interacts, is characteristic of many malignant tumors, raising the possibility that TGF-alpha acts to stimulate VPF/VEGF expression in other types of epithelial cells and in this manner induces angiogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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            Disruption of the mouse L1 gene leads to malformations of the nervous system.

            The adhesion molecule L1 is a member of the immunoglobulin superfamily. L1 is involved in various recognition processes in the CNS and PNS, and binding to L1 can activate signal transduction pathways. Mutations in the human L1 gene are associated with a variable phenotype, including mental retardation and anomalous development of the nervous system, referred to as 'CRASH' (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus). We generated an animal model of these conditions by gene targetting. Mutant mice were smaller than wild-type and were less sensitive to touch and pain, and their hind-legs appeared weak and uncoordinated. The size of the corticospinal tract was reduced and, depending on genetic background, the lateral ventricles were often enlarged. Non-myelinating Schwann cells formed processes not associated with axons and showed reduced association with axons. In vitro, neurite outgrowth on an L1 substrate and fasciculation were impaired. The mutant mouse described here will help to elucidate the functions of L1 in the nervous system and how these depend on genetic influences.
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              Neural adhesion molecule L1 as a member of the immunoglobulin superfamily with binding domains similar to fibronectin.

               D Teplow,  M Moos,  H Scherer (1988)
              Diverse glycoproteins of cell surfaces and extracellular matrices operationally termed 'adhesion molecules' are important in the specification of cell interactions during development, maintenance and regeneration of the nervous system. These adhesion molecules have distinct functions involving different cells at different developmental stages, but may cooperate when expressed together. Families of adhesion molecules which share common carbohydrate domains do exist, despite the structural and functional diversity of these glycoproteins. These include the Ca2+-independent neural adhesion molecules: N-CAM, myelin associated glycoprotein (MAG) and L1. L1 is involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, cerebellar granule cell migration, neurite outgrowth on Schwann cells and interactions among epithelial cells of intestinal crypts. We show here that in addition to sharing carbohydrate epitopes with N-CAM and MAG, L1 is also a member of the immunoglobulin superfamily. It contains six C2 domains and also shares three type III domains with the extracellular matrix adhesion molecule fibronectin.
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                Author and article information

                Affiliations
                [a ]Department of Pediatrics, University of California at San Diego, La Jolla, California 92037
                [b ]Department of Immunology, The Scripps Research Institute, La Jolla, California 92037
                [c ]Lung Biology Center, Center for Occupational and Environmental Health, Cardiovascular Research Institute,
                [d ]Department of Medicine, University of California, San Francisco, California 94080
                Contributors
                Journal
                J Cell Biol
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                26 June 2000
                : 149
                : 7
                : 1485-1502
                2175144
                9912057
                10871287
                © 2000 The Rockefeller University Press
                Categories
                Original Article

                Cell biology

                α5β1, α9β1, heterophilic ligation, melanoma, αvβ3, neural cam

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