<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Molecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity"^^ . "\r\nWnt/β-catenin signaling plays a critical role in animal development and adult tissue \r\nhomeostasis, including regulation of cell fate decisions, axial pattering, organogenesis\r\nand stem cell maintenance. Deregulation of Wnt signaling causes many human\r\ndiseases, including cancer and osteoporosis. Wnt proteins constitute a large family of\r\ngrowth factors characterized by conserved cysteine and a lipid modification at their\r\nN-terminal half. Upon transport through a specialized secretary route they act as\r\nmorphogens in variety of tissues by forming concentration gradient in the\r\nextracellular space. The post-translational addition of palmitate or palmitoic acid to\r\nWnts renders them highly hydrophobic and is believed to control their membrane\r\nlocalization, it is unknown, however, how Wnts are recruited from the membrane to\r\nsignaling complexes and how their signaling range is regulated.\r\nWnts bind to Frizzled (Fz) seven transmembrane receptors and LRP5/6 co-receptors,\r\nwhich leads to stabilization of the transcription coactivation of β-catenin and\r\nactivation of target gene. The structural basis of Wnt signaling by receptor binding\r\nhas long been elusive. Only recently, the crystal structure of the Xenopus Wnt8-\r\nFrizzled8-CRD complex was solved, but the significance of the interaction sites for\r\nsignaling has not been assessed. In the present thesis, by using a structure-based\r\nmutagenesis approach, I present an extensive structure-function analysis of mouse\r\nWnt3a by in vitro and in vivo evaluation. Evidence is provided for an essential role of\r\nSerine 209, Glycine 210 (site 1) and Tryptophan 333 (site 2) in Fz binding.\r\nImportantly, I discovered that Valine 337 in the site 2 binding loop is critical for\r\nsignaling without contributing to binding. Mutations in the presumptive second CRDbinding\r\nsite (site 3) partly abolished Wnt binding, suggesting Fz dimerization as a\r\nnecessary step in signaling. Intriguingly, most site 3 mutations increased Wnt\r\nsignaling, probably by inhibiting Wnt-CRD oligomerization. In accordance, it was\r\nobserved that increasing amounts of soluble Fz8-CRD protein modulated Wnt3a\r\nsignaling in a biphasic manner. Based on these finding, a model was developed, in\r\nwhich a concentration-dependent switch in Wnt-CRD complex formation from an\r\ninactive aggregation state to an activated, high mobility state, represents a modulatory\r\nmechanism in Wnt signaling gradients."^^ . "2014" . . . . "University of Heidelberg"^^ . . . . . . "Sumit "^^ . "Kumar"^^ . "Sumit Kumar"^^ . . . . . . "Molecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity (PDF)"^^ . . . "PhD thesis-Sumit Kumar.pdf"^^ . . . "Molecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity (Other)"^^ . . . . . . "small.jpg"^^ . . . "Molecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Molecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Molecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Molecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity (Other)"^^ . . . . . . "lightbox.jpg"^^ . . "HTML Summary of #16546 \n\nMolecular Dissection of Mouse Wnt3a-Frizzled8 Interaction Reveals Essential and Modulatory Determinants of Wnt Signaling Activity\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .