Fibronectin type III (FN3) modules of the neuronal cell adhesion molecule L1 interact directly with the fibroblast growth factor (FGF) receptor

Kulahin, Nikolaj; Li, Shizhong; Hinsby, Anders M.; Kiselyov, Vladislav V.; Berezin, Vladimir; Bock, Elisabeth

doi:10.1016/j.mcn.2007.12.001

Cited by 64 publications

(64 citation statements)

References 58 publications

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“…The mechanistic involvement of L1CAM in tumor progression was partially explained through the heterophilic interaction between L1CAM and integrins (13,14). In addition, an association between fibroblast growth factor and L1CAM function was also shown (15). Taken together, these observations suggest that L1CAM may play a role in tumor progression in a subset of human cancers.…”

Section: Introductionmentioning

confidence: 77%

Aberrant L1 Cell Adhesion Molecule Affects Tumor Behavior and Chemosensitivity in Anaplastic Thyroid Carcinoma

Kim

Min

Liang

et al. 2012

Clinical Cancer Research

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Purpose: Anaplastic thyroid carcinoma (ATC) is one of the most invasive human cancers and has a poor prognosis. Molecular targets of ATC that determine its highly aggressive nature remain unidentified. This study investigated L1 cell adhesion molecule (L1CAM) expression and its role in tumorigenesis of ATCs.Experimental Design: Expression of L1CAM in thyroid cancer was evaluated by immunohistochemical analyses of tumor samples from patients with thyroid cancer. We investigated the role of L1CAM in proliferation, migration, invasion, and chemoresistance using short hairpin RNA (shRNA) knockdown experiments in human ATC cell lines. Finally, we evaluated the role of L1CAM on tumorigenesis with ATC xenograft assay in a nude mouse model.Results: L1CAM expression was not detectable in normal follicular epithelial cells of the thyroid or in differentiated thyroid carcinoma. In contrast, analysis of ATC samples showed specifically higher expression of L1CAM in the invasive area of the tumor. Specific knockdown of L1CAM in the ATC cell lines, FRO and 8505C, caused a significant decrease in the proliferative, migratory, and invasive capabilities of the cells. Suppression of L1CAM expression in ATC cell lines increased chemosensitivity to gemcitabine or paclitaxel. Finally, in an ATC xenograft model, depletion of L1CAM markedly reduced tumor growth and increased the survival of tumor-bearing mice.Conclusions: We report that L1CAM is highly expressed in the samples taken from patients with ATCs. L1CAM plays an important role in determining tumor behavior and chemosensitivity in cell lines derived from ATCs. Therefore, we suggest that L1CAM may be an important therapeutic target in patients with ATCs.

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Section: Introductionmentioning

confidence: 77%

Aberrant L1 Cell Adhesion Molecule Affects Tumor Behavior and Chemosensitivity in Anaplastic Thyroid Carcinoma

Kim

Min

Liang

et al. 2012

Clinical Cancer Research

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“…Neural cell adhesion molecule (N-CAM), neuronal cadherin (N-cadherin) and L1 can activate FGFR1-2 in the absence of canonical FGFR ligands and this interaction is mediated by the acid box motif in the linker region between the D1 and D2 Ig-like loops of the receptor [27]. Therefore, N-CAM and N-cadherin act as a nonconventional FGFR1 ligand, promote receptor stabilization and exert a peculiar control on FGFR intracellular trafficking [28]. Extracellular matrix-associated glycoprotein anosmin-1 binds FGFR1 in a HS-dependent manner, modulating FGFR signalling during development [29].…”

Section: Fibroblast Growth Factor Receptorsmentioning

confidence: 99%

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Giacomini

Chiodelli

Matarazzo

et al. 2016

Pharmacological Research

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a b s t r a c tFibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments.The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies.Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising.Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

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“…Because there is growing evidence showing that FnIII domains in NCAM and L1 are involved in direct FGFR1 binding (19,20), we sought to determine whether the N-terminal region (CR and WAP) of anosmin-1 was required for the FGFR1 binding by testing the PIF4 construct, which contains only the four FnIII domains. In addition, we introduced three point mutations (N267K, E514K, and F517L) into the fulllength PIWF4 to investigate the effects of KS-related missense mutations in the FnIII domains.…”

Section: Determination Of Direct Binding Of Anosmin-1 To Fgfr1-mentioning

confidence: 99%

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

Guimond

Travers

et al. 2009

Journal of Biological Chemistry

101

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Activation of fibroblast growth factor (FGF) signaling is initiated by a multiprotein complex formation between FGF, FGF receptor (FGFR), and heparan sulfate proteoglycan on the cell membrane. Cross-talk with other factors could affect this complex assembly and modulate the biological response of cells to FGF. We have previously demonstrated that anosmin-1, a glycosylated extracellular matrix protein, interacts with the FGFR1 signaling complex and enhances its activity in an IIIc isoformspecific and HS-dependent manner. The molecular mechanism of anosmin-1 action on FGFR1 signaling, however, remains unknown. Here, we show that anosmin-1 directly binds to FGFR1 with high affinity. This interaction involves domains in the N terminus of anosmin-1 (cysteine-rich region, whey acidic protein-like domain and the first fibronectin type III domain) and the D2-D3 extracellular domains of FGFR1. In contrast, anosmin-1 binds to FGFR2IIIc with much lower affinity and displays negligible binding to FGFR3IIIc. We also show that FGFR1-bound anosmin-1, although capable of binding to FGF2 alone, cannot bind to a FGF2⅐heparin complex, thus preventing FGFR1⅐FGF2⅐heparin complex formation. By contrast, heparinbound anosmin-1 binds to pre-formed FGF2⅐FGFR1 complex, generating an anosmin-1⅐FGFR1⅐FGF2⅐heparin complex. Furthermore, a functional interaction between anosmin-1 and the FGFR1 signaling complex is demonstrated by immunofluorescence co-localization and Transwell migration assays where anosmin-1 was shown to induce opposing effects during chemotaxis of human neuronal cells. Our study provides molecular and cellular evidence for a modulatory action of anosmin-1 on FGFR1 signaling, whereby binding of anosmin-1 to FGFR1 and heparin can play a dual role in assembly and activity of the ternary FGFR1⅐FGF2⅐heparin complex. FGF5 signaling plays an important role in a wide range of fundamental biological responses (1-3). Both FGF and FGFR bind to heparan sulfate (HS) and heparin, a highly sulfated type of HS produced in connective tissue mast cells. Heparan sulfate proteoglycans (HSPG) are the cell surface co-receptors essential for the formation of functional FGF⅐FGFR signaling complex (4, 5). There are four structurally related FGFRs (FGFR1-4), which consist of an extracellular ligand-binding region containing three immunoglobulin (Ig)-like domains (D1-D3), a single transmembrane domain, and a cytoplasmic domain with protein-tyrosine kinase catalytic activity. The 22 members of the FGF family bind to the interface formed by the D2/D3 domains and the linker between these domains (6, 7), whereas a conserved positively charged region in D2 serves as the HS binding site (8). An unusual stretch of seven to eight acidic residues designated as the "acid box" is present in the linker connecting D1 and D2. Alternative splicing events occur to generate various isoforms, including a truncated receptor lacking D1 and the D1-D2 linker or a full-length receptor that differs in the second half of D3, designated as IIIb and IIIc isoforms (5). Two cry...

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Fibronectin type III (FN3) modules of the neuronal cell adhesion molecule L1 interact directly with the fibroblast growth factor (FGF) receptor

Cited by 64 publications

References 58 publications

Aberrant L1 Cell Adhesion Molecule Affects Tumor Behavior and Chemosensitivity in Anaplastic Thyroid Carcinoma

Aberrant L1 Cell Adhesion Molecule Affects Tumor Behavior and Chemosensitivity in Anaplastic Thyroid Carcinoma

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

Novel Mechanisms of Fibroblast Growth Factor Receptor 1 Regulation by Extracellular Matrix Protein Anosmin-1

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