Activation of EGF Receptor Kinase by L1-mediated Homophilic Cell Interactions

Rafique, Islam; Kristiansen, Lars V.; Romani, Susana; García‐Alonso, Luis; Hortsch, Michael

doi:10.1091/mbc.e03-05-0333

Cited by 74 publications

(101 citation statements)

References 51 publications

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“…The initial activation of the EGF receptor could be initiated in a ligand-independent manner. The broadly expressed adhesion protein Neuroglian is not only a core component of septate junctions but is also known to activate receptor tyrosine kinase signaling in a ligand-independent manner (Doherty and Walsh, 1996;Donier et al, 2012;García-Alonso et al, 2000;Gibson and Tolbert, 2006;Gibson et al, 2012;Islam et al, 2004;Kristiansen et al, 2005;Nagaraj et al, 2009). Possibly, Neuroglian might thus deliver a first trigger signal to initiate glial differentiation, independent of activating ligands such as Vein or Spitz.…”

Section: Discussionmentioning

confidence: 99%

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

et al. 2015

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Efficient neuronal conductance requires that axons are insulated by glial cells. For this, glial membranes need to wrap around axons. Invertebrates show a relatively simple extension of glial membranes around the axons, resembling Remak fibers formed by Schwann cells in the mammalian peripheral nervous system. To unravel the molecular pathways underlying differentiation of glial cells that provide axonal wrapping, we are using the genetically amenable Drosophila model. At the end of larval life, the wrapping glia differentiates into very large cells, spanning more than 1 mm of axonal length. The extension around axonal membranes is not influenced by the caliber of the axon or its modality. Using cell typespecific gene knockdown we show that the extension of glial membranes around the axons is regulated by an autocrine activation of the EGF receptor through the neuregulin homolog Vein. This resembles the molecular mechanism employed during cell-autonomous reactivation of glial differentiation after injury in mammals. We further demonstrate that Vein, produced by the wrapping glia, also regulates the formation of septate junctions in the abutting subperineurial glia. Moreover, the wrapping glia indirectly controls the proliferation of the perineurial glia. Thus, the wrapping glia appears center stage to orchestrate the development of the different glial cell layers in a peripheral nerve.

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Section: Discussionmentioning

confidence: 99%

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

et al. 2015

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“…Given that EGF has also been shown to regulate neurite outgrowth (Martinez and Gomes, 2002;Povlsen et al, 2008) and that L1-CAM-mediated cell adhesion activates EGFR tyrosine kinase (Islam et al, 2004), we next tested whether EGFR signaling is involved in ␤1-dependent neurite outgrowth, using the EGFR inhibitor AG1478. In a control experiment, the activity of AG1478 was confirmed by assessing its dose-dependent effect on the proliferation of N/TERT human keratinocytes.…”

Section: Inhibition Of Fgfr and Egfr Signaling Does Not Affect ␤1-medmentioning

confidence: 99%

Voltage-Gated Na⁺Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

Brackenbury¹,

Davis²,

Chen³

et al. 2008

J. Neurosci.

176

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Voltage-gated Naϩ channel ␤1 subunits are multifunctional, participating in channel modulation and cell adhesion in vitro. We previously demonstrated that ␤1 promotes neurite outgrowth of cultured cerebellar granule neurons (CGNs) via homophilic adhesion. Both lipid raft-associated kinases and nonraft fibroblast growth factor (FGF) receptors are implicated in cell adhesion molecule-mediated neurite extension. In the present study, we reveal that ␤1-mediated neurite outgrowth is abrogated in Fyn and contactin (Cntn) null CGNs. ␤1 protein levels are unchanged in Fyn null brains, whereas levels are significantly reduced in Cntn null brain lysates. FGF or EGF (epidermal growth factor) receptor kinase inhibitors have no effect on ␤1-mediated neurite extension. These results suggest that ␤1-mediated neurite outgrowth occurs through a lipid raft signaling mechanism that requires the presence of both fyn kinase and contactin. In vivo, Scn1b null mice show defective CGN axon extension and fasciculation indicating that ␤1 plays a role in cerebellar microorganization. In addition, we find that axonal pathfinding and fasciculation are abnormal in corticospinal tracts of Scn1b null mice consistent with the suggestion that ␤1 may have widespread effects on postnatal neuronal development. These data are the first to demonstrate a cell-adhesive role for ␤1 in vivo. We conclude that voltage-gated Na ϩ channel ␤1 subunits signal via multiple pathways on multiple timescales and play important roles in the postnatal development of the CNS.

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“…This is suggested by the findings that L1-mediated cell adhesion activates the fibroblast growth factor (FGF) receptor (19) and the epidermal growth factor (EGF) receptor (20) tyrosine phosphorylation, respectively, the latter an effect which appears to involve L1/EGF receptor trans interactions (20). On the other hand, the cytoplasmic domain of L1 contains several phosphorylation sites and it was shown before that phosphorylation events induced by growth factors regulate the interaction of the L1 family member neurofascin with the ankyrin/actin network and L1 lateral movement (21)(22)(23).…”

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confidence: 99%

Hepatocyte Growth Factor-induced Ectodomain Shedding of Cell Adhesion Molecule L1

Heiz

Grünberg

Schubiger

et al. 2004

Journal of Biological Chemistry

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The L1 cell adhesion molecule and its soluble form are tumor-associated proteins and potential markers for tumor staging as well as targets for therapeutic intervention. Soluble L1 is produced by metalloprotease-mediated ectodomain shedding of L1. We investigated effects of hepatocyte growth factor (HGF), a growth factor shown to increase invasiveness of renal carcinoma cells, on ectodomain shedding of L1 from these cells. All of the tested L1-positive renal carcinoma cell lines released a 180-kDa form of L1 into the medium. In the presence of serum, addition of HGF led to a dose-dependent increase in L1 shedding with a maximum reached at 5 ng/ml. In contrast, L1 shedding was inhibited by glial cell linederived neurotrophic factor (GDNF). The tyrosine kinase inhibitor Genistein reduced basal and HGFstimulated L1 shedding, indicating that protein phosphorylation is involved. To investigate the role of the L1 intracellular domain, two mutants of the L1 cytoplasmic part were constructed. L1trun lacking the complete intracellular domain showed enhanced basal shedding. In a L1YH mutant, containing the mutation tyrosine 1229 to histidine that deletes the ankyrin binding motif of L1, basal shedding was reduced. Disruption of actin assembly by cytochalasin D also reduced shedding of L1. These results indicate that the cytoplasmic domain regulates basal shedding of L1, and association with the cytoskeleton through the L1 ankyrin binding site is involved. HGF stimulated L1 shedding in both mutants, indicating that receptor-mediated phosphorylation in the L1 cytoplasmic domain is not required for HGF-stimulated shedding.The L1 cell adhesion molecule (L1) 1 was originally described as a protein of the nervous system, and mutated forms of L1 are linked to severe neurological pathologies referred to as MASA syndrome (1). A non-neuronal isoform of L1 lacking exons 2 and 27 is expressed at low levels in the normal adult human kidney (2) as well as during renal development (3). In contrast, high expression of L1 was found in 8 of 12 renal tumor cell lines and in some renal tumors (2). 2 It was shown that the cell-bound form of L1 can serve as a target for radioimmunodiagnosis of metastatic neuroblastoma (4), and L1 may also be a marker and therapeutic target for certain renal cancers.In cultured cell lines originating from a number of different tumors the L1 ectodomain was found to be cleaved proximal to the cell membrane by metalloproteases, followed by release of soluble L1 into the medium (5-7). Ectodomain shedding of L1 could be stimulated by phorbol esters and vanadate, indicating that phosphorylation events regulate L1 release (6). In cell culture soluble L1 substrate was found to stimulate cellular motility and migration (8). Release of soluble L1 is not restricted to cells in culture as soluble L1 was recently detected in serum samples of patients with ovarian and uterine tumors and is believed to lead to increased cell migration and metastatic spread in these malignancies (9).Here we investigated whether hepatocyte grow...

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Activation of EGF Receptor Kinase by L1-mediated Homophilic Cell Interactions

Cited by 74 publications

References 51 publications

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

Voltage-Gated Na⁺Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

Hepatocyte Growth Factor-induced Ectodomain Shedding of Cell Adhesion Molecule L1

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Activation of EGF Receptor Kinase by L1-mediated Homophilic Cell Interactions

Cited by 74 publications

References 51 publications

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

Voltage-Gated Na+Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo

Hepatocyte Growth Factor-induced Ectodomain Shedding of Cell Adhesion Molecule L1

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Voltage-Gated Na⁺Channel β1 Subunit-Mediated Neurite Outgrowth Requires Fyn Kinase and Contributes to Postnatal CNS DevelopmentIn Vivo