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  • Trans-Activation between EphA and FGFR Regulates Self-Renewal and Differentiation of Mouse Embryonic Neural Stem/Progenitor Cells via Differential Activation of FRS2α. 26024354

    Ephs and FGFRs belong to a superfamily of receptor tyrosine kinases, playing important roles in stem cell biology. We previously reported that EphA4 and FGFR form a heterodimer following stimulation with ligands, trans-activating each other and signaling through a docking protein, FRS2α, that binds to both receptors. Here, we investigated whether the interaction between EphA4 and FGFRs can be generalized to other Ephs and FGFRs, and, in addition, examined the downstream signal mediating their function in embryonic neural stem/progenitor cells. We revealed that various Ephs and FGFRs interact with each other through similar molecular domains. When neural stem/progenitor cells were stimulated with FGF2 and ephrin-A1, the signal transduced from the EphA4/FGFR/FRS2α complex enhanced self-renewal, while stimulation with ephrin-A1 alone induced neuronal differentiation. The downstream signal required for neuronal differentiation appears to be MAP kinase mainly linked to the Ras family of G proteins. MAP kinase activation was delayed and sustained, distinct from the transient activation induced by FGF2. Interestingly, this effect on neuronal differentiation required the presence of FGFRs. Specific FGFR inhibitor almost completely abolished the function of ephrin-A1 stimulation. These findings suggest that the ternary complex of EphA, FGFR and FRS2α formed by ligand stimulation regulates self-renewal and differentiation of mouse embryonic neural stem/progenitor cells by ligand-specific fine tuning of the downstream signal via FRS2α.
    Document Type:
    Reference
    Product Catalog Number:
    05-321
    Product Catalog Name:
    Anti-Phosphotyrosine Antibody, clone 4G10®

  • Fibroblast growth factor receptor (FGFR) and candidate signaling molecule distribution within rat and human retina. 12097864

    PURPOSE: To map the expression and distribution of FGFR and potential FGFR-related signaling molecules within rat and human retina. METHODS: Sections of postnatal 5 day old and adult rat, and aged human retina, and cell cultures prepared from selected cell populations of young rat retina, were immunolabeled with specific antisera to FGFR (FGFR-1, -2, -3, and -4) or candidate signaling molecules [phospholipase Cg1 (PLCg1), son of sevenless 1 and 2 (SOS1, SOS2), extracellular signal-regulated kinase 1 and 2 (ERK1/2), protein tyrosine phosphatase (SH-PTP2) and SH2-containing protein (Shc)], and with multiple retinal cell-type specific antibodies. Controls were conducted using primary antisera pre-adsorbed with the corresponding immunizing peptide. RESULTS: All FGFR antisera showed strong labeling of inner retina [inner nuclear layer, inner plexiform layer and ganglion cell layer (INL, IPL and GCL respectively)] in rat and human retina, although there were distinct differences in individual patterns. FGFR-3 was particularly intense in ganglion cell bodies and dendrites, and was absent from photoreceptors and bipolar cells in vitro. FGFR-1 and FGFR-4 also labeled the outer nuclear layer (ONL), more intensely in adult than in young tissue, and FGFR-4 was especially prominent within inner segments. FGFR-2 and -3 were only weakly expressed in the ONL, but FGFR-2 showed specific labeling of cone outer segments in human retina. Candidate FGFR-signaling molecules also showed generally higher expression in the inner than outer retina in the different samples. Shc immunolabeling was apparent in the GCL and nascent photoreceptor outer segments in young and adult retina. SOS1 expression was much more intense than SOS2 in the ONL, although the latter showed selective intense staining of a sub-population in the INL and GCL. These ex vivo data were confirmed in cultures prepared from young rat retina. Pure photoreceptor cultures exhibited strong expression of FGFR-1 and -4, and faint expression of FGFR-2 and -3. In mixed inner retinal cultures, anti-FGFR-1 labeled neurons and Müller glia with equal intensity, while the other FGFR antisera showed preferential staining of neurons. FGFR-3 was strongly expressed by ganglion and amacrine cells but not by other types. Signaling molecules showed widespread expression, but of variable intensity, in all cells. All control experiments using corresponding peptide pre-adsorption led to complete removal of immunostaining. CONCLUSIONS: Rat and human retinal cells showed a largely similar, widespread expression of multiple FGFR and candidate FGFR-related signaling molecules. Distinct differences in development, species, cell- and sub-cell type distribution were apparent, suggesting that specific FGFR/FGF ligands and transduction pathways may operate in different cells.
    Document Type:
    Reference
    Product Catalog Number:
    06-203

  • S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab. 23804704

    Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.
    Document Type:
    Reference
    Product Catalog Number:
    MAB1501R
    Product Catalog Name:
    Anti-Actin Antibody,clone C4

  • betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. 18187602

    Fibroblast growth factor (FGF) 21, a structural relative of FGF23 that regulates phosphate homeostasis, is a regulator of insulin-independent glucose transport in adipocytes and plays a role in the regulation of body weight. It also regulates ketogenesis and adaptive responses to starvation. We report that in a reconstituted receptor activation assay system using BaF3 cells, which do not endogenously express any type of FGF receptor (FGFR) or heparan sulfate proteoglycan, FGF21 alone does not activate FGFRs and that betaKlotho is required for FGF21 to activate two specific FGFR subtypes: FGFR1c and FGFR3c. Coexpression of betaKlotho and FGFR1c on BaF3 cells enabled FGF21, but not FGF23, to activate receptor signaling. Conversely, coexpression of FGFR1c and Klotho, a protein related to betaKlotho, enabled FGF23 but not FGF21 to activate receptor signaling, indicating that expression of betaKlotho/Klotho confers target cell specificity on FGF21/FGF23. In all of these cases, heparin enhanced the activation but was not essential. In 3T3-L1 adipocytes, up-regulation of glucose transporter (GLUT) expression by FGF21 was associated with expression of betaKlotho, which was absent in undifferentiated 3T3-L1 fibroblasts. It is thus suggested that betaKlotho expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion.
    Document Type:
    Reference
    Product Catalog Number:
    AP181P
    Product Catalog Name:
    Goat Anti-Mouse IgG Antibody, HRP conjugate, Species Adsorbed

  • Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. 18068632

    Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.
    Document Type:
    Reference
    Product Catalog Number:
    06-680
    Product Catalog Name:
    Anti-Androgen Receptor Antibody

  • Activation of glial FGFRs is essential in glial migration, proliferation, and survival and in glia-neuron signaling during olfactory system development. 22493675

    Development of the adult olfactory system of the moth Manduca sexta depends on reciprocal interactions between olfactory receptor neuron (ORN) axons growing in from the periphery and centrally-derived glial cells. Early-arriving ORN axons induce a subset of glial cells to proliferate and migrate to form an axon-sorting zone, in which later-arriving ORN axons will change their axonal neighbors and change their direction of outgrowth in order to travel with like axons to their target areas in the olfactory (antennal) lobe. These newly fasciculated axon bundles will terminate in protoglomeruli, the formation of which induces other glial cells to migrate to surround them. Glial cells do not migrate unless ORN axons are present, axons fail to fasciculate and target correctly without sufficient glial cells, and protoglomeruli are not maintained without a glial surround. We have shown previously that Epidermal Growth Factor receptors and the IgCAMs Neuroglian and Fasciclin II play a role in the ORN responses to glial cells. In the present work, we present evidence for the importance of glial Fibroblast Growth Factor receptors in glial migration, proliferation, and survival in this developing pathway. We also report changes in growth patterns of ORN axons and of the dendrites of olfactory (antennal lobe) neurons following blockade of glial FGFR activation that suggest that glial FGFR activation is important in reciprocal communication between neurons and glial cells.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2. 17297442

    The expression of fibroblast growth factor receptor (FGFR)-1 correlates with angiogenesis and is associated with prostate cancer (CaP) progression. To more precisely define the molecular mechanisms whereby FGFR1 causes angiogenesis in the prostate we exploited a transgenic mouse model, JOCK-1, in which activation of a conditional FGFR1 allele in the prostate epithelium caused rapid angiogenesis and progressive hyperplasia. By labeling the vasculature in vivo and applying a novel method to measure the vasculature in three dimensions, we were able to observe a significant increase in vascular volume 1 week after FGFR1 activation. Although vessel volume and branching both continued to increase throughout a 6-week period of FGFR1 activation, importantly, we discovered that continued activation of FGFR1 was not required to maintain the new vasculature. Exploring the molecular mediators of the angiogenic phenotype, we observed consistent upregulation of HIF-1alpha, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2), whereas expression of Ang-1 was lost. Further analysis revealed that loss of Ang-1 expression occurred in the basal epithelium, whereas the increase in Ang-2 expression occurred in the luminal epithelium. Reporter assays confirmed that the Ang-2 promoter was regulated by FGFR1 signaling and a small molecule inhibitor of FGFR activity, PD173074, could abrogate this response. These findings establish a method to follow spontaneous angiogenesis in a conditional autochthonous system, implicate the angiopoietins as downstream effectors of FGFR1 activation in vivo, and suggest that therapies targeting FGFR1 could be used to inhibit neovascularization during initiation and progression of CaP.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • The neural cell adhesion molecule promotes FGFR-dependent phosphorylation and membrane targeting of the exocyst complex to induce exocytosis in growth cones. 21389209

    The exocyst complex is an essential regulator of polarized exocytosis involved in morphogenesis of neurons. We show that this complex binds to the intracellular domain of the neural cell adhesion molecule (NCAM). NCAM promotes FGF receptor-mediated phosphorylation of two tyrosine residues in the sec8 subunit of the exocyst complex and is required for efficient recruitment of the exocyst complex to growth cones. NCAM at the surface of growth cones induces Ca(2+)-dependent vesicle exocytosis, which is blocked by an inhibitor of L-type voltage-dependent Ca(2+) channels and tetanus toxin. Preferential exocytosis in growth cones underlying neurite outgrowth is inhibited in NCAM-deficient neurons as well as in neurons transfected with phosphorylation-deficient sec8 and dominant-negative peptides derived from the intracellular domain of NCAM. Thus, we reveal a novel role for a cell adhesion molecule in that it regulates addition of the new membrane to the cell surface of growth cones in developing neurons.
    Document Type:
    Reference
    Product Catalog Number:
    MABT186
    Product Catalog Name:
    Anti-Exo70 Antibody, clone 70X13F3

  • FGF signalling through Fgfr2 isoform IIIb regulates adrenal cortex development. 23376610

    Developmental signalling pathways are implicated in the formation and maintenance of the adrenal gland, but their roles are currently not well defined. In recent years it has emerged that Sonic hedgehog (Shh) and Wnt/β catenin signalling are crucial for the growth and development of the adrenal cortex. Here we demonstrate that Fibroblast growth factor receptor (Fgfr) 2 isoforms IIIb and IIIc are expressed mainly in the adrenal subcapsule during embryogenesis and that specific deletion of the Fgfr2 IIIb isoform impairs adrenal development, causing reduced adrenal growth and impaired expression of SF1 and steroidogenic enzymes. The hypoplastic adrenals also have thicker, disorganised capsules which retain Gli1 expression but no longer express Dlk1. Fgfr2 ligands were detected in both the capsule and the cortex, suggesting the importance of signalling between the capsule and the cortex in adrenal development.
    Document Type:
    Reference
    Product Catalog Number:
    AB1244

  • Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F. 16844695

    Fibroblast growth factors (FGFs) and their receptors (FGFRs) are known to play a critical role in a variety of fundamental processes, including wound healing, angiogenesis, and development of multiple organ systems. Mutations in the FGFR gene family have been linked to a series of syndromes (the craniosynostosis syndromes) whose primary phenotype involves aberrant development of the craniofacial skeleton. Craniosynostosis syndrome-linked FGFR mutations have been shown to be gain of function in terms of receptor activation and have been presumed to result in increased levels of FGF/FGFR signaling. Unfortunately, studies attempting to link expression of mutant FGFRs with changes in cellular phenotype have yielded conflicting results. In an effort to better understand the biochemical consequences of these mutations on receptor function, here we have investigated the effect of the FGFR2C278F mutation of Crouzon craniosynostosis syndrome on receptor trafficking, ubiquitination, degradation, and signaling. We find that FGFR2C278F exhibits diminished glycosylation, increased degradation, and limited cellular sublocalization in the osteoblastic cell line, MC3T3E1(C4). Additionally, we show that trafficking and autoactivation of wild type FGFR2 is glycosylation-dependent. Both FGFR2C278F and unglycosylated wild type FGFR2 signal through phospholipase Cgamma in a ligand-independent manner as well as exhibit dramatically increased binding to the adaptor protein, Frs2. These findings suggest that autoactive FGFR2 can signal from intracellular compartments. Based upon our results, we propose that the functional signaling of craniosynostosis mutant, autoactive receptors is limited in some cell types by protective cellular responses, such as increased trafficking to lysosomes and proteasomes for degradation.
    Document Type:
    Reference
    Product Catalog Number:
    AB1690
    Product Catalog Name:
    Anti-Ubiquitin Antibody