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  • 1
    Online Resource
    Online Resource
    Fibroblast growth factor receptor 2 tyrosine kinase is required for prostatic morphogenesis and the acquisition of strict androgen dependency for adult tissue homeostasis
    The Company of Biologists ; 2007
    In:  Development Vol. 134, No. 4 ( 2007-02-15), p. 723-734
    Details
    In: Development, The Company of Biologists, Vol. 134, No. 4 ( 2007-02-15), p. 723-734
    Abstract: The fibroblast growth factor (FGF) family consists of 22 members and regulates a broad spectrum of biological activities by activating diverse isotypes of FGF receptor tyrosine kinases (FGFRs). Among the FGFs, FGF7 and FGF10 have been implicated in the regulation of prostate development and prostate tissue homeostasis by signaling through the FGFR2 isoform. Using conditional gene ablation with the Cre-LoxP system in mice, we demonstrate a tissue-specific requirement for FGFR2 in urogenital epithelial cells - the precursors of prostatic epithelial cells - for prostatic branching morphogenesis and prostatic growth. Most Fgfr2 conditional null(Fgfr2cn) embryos developed only two dorsal prostatic (dp)and two lateral prostatic (lp) lobes. This contrasts to wild-type prostate,which has two anterior prostatic (ap), two dp, two lp and two ventral prostatic (vp) lobes. Unlike wild-type prostates, which are composed of well developed epithelial ductal networks, the Fgfr2cnprostates, despite retaining a compartmented tissue structure, exhibited a primitive epithelial architecture. Moreover, although Fgfr2cn prostates continued to produce secretory proteins in an androgen-dependent manner, they responded poorly to androgen with respect to tissue homeostasis. The results demonstrate that FGFR2 is important for prostate organogenesis and for the prostate to develop into a strictly androgen-dependent organ with respect to tissue homeostasis but not to the secretory function, implying that androgens may regulate tissue homeostasis and tissue function differently. Therefore, Fgfr2cnprostates provide a useful animal model for scrutinizing molecular mechanisms by which androgens regulate prostate growth, homeostasis and function, and may yield clues as to how advanced-tumor prostate cells escape strict androgen regulations.
    Type of Medium: Online Resource
    ISSN: 1477-9129 , 0950-1991
    URL: Article
    DOI: 10.1242/dev.02765
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2007
    detail.hit.zdb_id: 2007916-3
    SSG: 12
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  • 2
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    Fibroblast Growth Factor Receptor 1 (FGFR1) Tyrosine Phosphorylation Regulates Binding of FGFR Substrate 2α (FRS2α) But Not FRS2β to the Receptor
    The Endocrine Society ; 2008
    In:  Molecular Endocrinology Vol. 22, No. 1 ( 2008-01-01), p. 167-175
    Details
    In: Molecular Endocrinology, The Endocrine Society, Vol. 22, No. 1 ( 2008-01-01), p. 167-175
    Abstract: Binding of the fibroblast growth factor (FGF) to the FGF receptor (FGFR) tyrosine kinase leads to receptor tyrosine autophosphorylation as well as phosphorylation of multiple downstream signaling molecules that are recruited to the receptor either by direct binding or through adaptor proteins. The FGFR substrate 2 (FRS2) family consists of two members, FRS2α and FRS2β, and has been shown to recruit multiple signaling molecules, including Grb2 and Shp2, to FGFR1. To better understand how FRS2 interacted with FGFR1, in vivo binding assays with coexpressed FGFR1 and FRS2 recombinant proteins in mammalian cells were carried out. The results showed that the interaction of full-length FRS2α, but not FRS2β, with FGFR1 was enhanced by activation of the receptor kinase. The truncated FRS2α mutant that was comprised only of the phosphotyrosine-binding domain (PTB) bound FGFR1 constitutively, suggesting that the C-terminal sequence downstream the PTB domain inhibited the PTB-FGFR1 binding. Inactivation of the FGFR1 kinase and substitutions of tyrosine phosphorylation sites of FGFR1, but not FRS2α, reduced binding of FGFR1 with FRS2α. The results suggest that although the tyrosine autophosphorylation sites of FGFR1 did not constitute the binding sites for FRS2α, phosphorylation of these residues was essential for optimal interaction with FRS2α. In addition, it was demonstrated that the Grb2-binding sites of FRS2α are essential for mediating signals of FGFR1 to activate the FiRE enhancer of the mouse syndecan 1 gene. The results, for the first time, demonstrate the specific signals mediated by the Grb2-binding sites and further our understanding of FGF signal transmission at the adaptor level.
    Type of Medium: Online Resource
    ISSN: 0888-8809 , 1944-9917
    URL: Article
    DOI: 10.1210/me.2007-0140
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2008
    detail.hit.zdb_id: 1492112-1
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