The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulates the Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells

Lu, Lingge; Magnusson, Peetra U.; Nyqvist, Daniel; Holmqvist, Kristina; Welsh, Michael J.; Claesson‐Welsh, Lena

doi:10.1091/mbc.e02-02-0103

Cited by 82 publications

(72 citation statements)

References 39 publications

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“…Partanen et al (Partanen et al, 1998) observed very similar axial transformations, but not polydactyly, by creating a hypermorphic point mutation Y766F in the putative PLCγ/Shb (Cross et al, 2002) docking site in Fgfr1. It is significant that this allele does not give rise to polydactyly, indicating that the underlying threshold-dependent pathways in limb and axial skeleton development are distinct.…”

Section: Morphogen Signalling In Cranial and Sternal Defectsmentioning

confidence: 99%

Skeletal development is regulated by fibroblast growth factor receptor 1 signalling dynamics

et al. 2004

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Ligand-dependent signalling pathways have been characterised as having morphogen properties where there is a quantitative relationship between receptor activation and response, or threshold characteristics in which there is a binary switch in response at a fixed level of receptor activation. Here we report the use of a bacterial artificial chromosome (BAC)-based transgenic system in which a hypermorphic mutation has been introduced into the murine Fgfr1 gene. These mice exhibit cranial suture and sternal fusions that are exacerbated when the BAC copy number is increased. Surprisingly,increasing mutant BAC copy number also leads to the de novo appearance of digit I polydactyly in the hind limb and transformations of the vertebrae. Polydactyly is accompanied by a reduction of programmed cell death in the developing hind limb. Candidate gene analysis reveals downregulation of Dkk1 in the digit I field and upregulation of Wnt5a and Hoxd13. These findings show that Fgfr1-mediated developmental pathways exhibit differing signalling dynamics, whereby development of the cranial sutures and sternum follows a morphogen mode, whereas development of the vertebral column and the hind limbs has threshold signalling properties.

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Section: Morphogen Signalling In Cranial and Sternal Defectsmentioning

confidence: 99%

Skeletal development is regulated by fibroblast growth factor receptor 1 signalling dynamics

et al. 2004

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“…Active Fgfrs can directly engage relatively few proteins, namely Crk, Grb14, Shb, PLC␥ and Frs2,3 (hereafter referred to collectively as 'Frs') (Mohammadi et al, 1991;Wang et al, 1996;Kouhara et al, 1997;Larrson et al, 1999;Reilly et al, 2000;Cross et al, 2002). Biochemical studies have implicated Frs adaptors as the key mediators of Fgfr signal transduction.…”

Section: Introductionmentioning

confidence: 99%

Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development

2006

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Fibroblast growth factor receptor 1 (Fgfr1) plays pleiotropic roles during embryonic development, but the mechanisms by which this receptor signals in vivo have not previously been elucidated. Biochemical studies have implicated Fgf receptor-specific substrates (Frs2, Frs3) as the principal mediators of Fgfr1 signal transduction to the MAPK and PI3K pathways. To determine the developmental requirements for Fgfr1-Frs signaling, we generated mice (Fgfr1 ⌬Frs/⌬Frs ) in which the Frs2/3-binding site on Fgfr1 is deleted. Fgfr1 ⌬Frs/⌬Frs embryos die during late embryogenesis, and exhibit defects in neural tube closure and in the development of the tail bud and pharyngeal arches. However, the mutant receptor is able to drive Fgfr1 functions during gastrulation and somitogenesis, and drives normal MAPK responses to Fgf. These findings indicate that Fgfr1 uses distinct signal transduction mechanisms in different developmental contexts, and that some essential functions of this receptor are mediated by Frsindependent signaling.

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“…Thymidine assay and coculture of cells. Thymidine assays were performed according to a standard proliferation protocol measuring [ 3 H]thymidine (1Ci/ml) incorporation (16). ECs were plated in 24-well plates, with 25 ϫ 10 3 cells/well in EC medium with supplements for 24 h and then cultured in EC medium without supplements but containing 0.5% fetal bovine serum (starvation medium) for an additional 24 h (basal control) or stimulated with either VEGF-A (20 ng/ml; Peprotech, London, U.K.) in starvation medium or MSCconditioned medium (supernatant from 24-h MSC cultures in starvation medium).…”

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confidence: 99%

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

et al. 2008

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OBJECTIVE-Mesenchymal stem cells (MSCs) contribute to endothelial cell (EC) migration by producing proteases, thereby paving the way into the tissues for ECs. MSCs were added to our previously described composite EC islets as a potential means to improve their capacity for islet angiogenesis.RESEARCH DESIGN AND METHODS-Human islets were coated with primary human bone marrow-derived MSCs and dermal microvascular ECs. The capacity of ECs, with or without MSCs, to adhere to and grow into human islets was analyzed. The survival and functionality of these composite islets were evaluated in a dynamic perifusion assay, and their capacity for angiogenesis in vitro was assessed in a three-dimensional fibrin gel assay.RESULTS-ECs proliferated after culture in MSC-conditioned medium, and MSCs improved the EC coverage threefold compared with EC islets alone. Islet survival in vitro and the functionality of the composite islets after culture were equal to those of control islets. The EC-MSC islets showed a twofold increase in total sprout formation compared with EC islets, and vascular sprouts emanating from the EC-MSC-islet surface showed migration of ECs into the islets and also into the surrounding matrix, either alone or in concert with MSCs. T he islets of Langerhans are micro-organs, with afferent and efferent blood vessels connecting the capillary network of the islets to the circulation system (1). Intra-islet endothelial cells (ECs) are fenestrated, and the density of the capillary network in the islets is ϳ10 times higher than that of the surrounding exocrine tissue (2,3). During the process of islet isolation before transplantation, the ECs in the islets lose their external vascular support; this situation contributes to their dedifferentiation, apoptosis, and necrosis during subsequent in vitro culture (4). CONCLUSIONS-ECThe formation of new capillaries during revascularization is a complex process that involves digestion of the vascular wall by proteases and the migration, proliferation, and differentiation of ECs (5). When blood vessels are assembled, ECs produce platelet-derived growth factor, which attracts supportive cells, including mesenchymal stem cells (MSCs) that can differentiate into pericytes (6).We hypothesized that adding MSCs to our previously described composite EC islets (7) might improve the adherence of the ECs to the islets and subsequent vascularization because MSCs contribute to EC migration by producing proteases, thereby paving the way into the surrounding tissue for the immature EC sprouts (8). MSCs have also been shown to upregulate the expression of angiopoietin and vascular endothelial growth factor (VEGF) in ECs, contributing to an increase in angiogenesis and stabilization of the vasculature (9). Moreover, MSCs have been shown to possess important immune-modulating properties (10), and they do not trigger adaptive immune reactions, which could make them ideal in islet transplantation setting (11,12).The present study describes a gentle and reproducible technique for forming EC-MSC i...

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The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulates the Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells

Cited by 82 publications

References 39 publications

Skeletal development is regulated by fibroblast growth factor receptor 1 signalling dynamics

Skeletal development is regulated by fibroblast growth factor receptor 1 signalling dynamics

Context-specific requirements for Fgfr1 signaling through Frs2 and Frs3 during mouse development

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

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