title: Differential Effects of Variations at Codon 106 on Sprouty2 Functions in Lung Cancer-Derived Cells.
abstract: Sprouty2 is a modulator of receptor tyrosine kinase-mediated signalling with an important role during lung carcinogenesis. Here, we characterize a Sprouty2 variant harbouring a substitution of proline 106 with serine. Serine substitution fails to influence expression, but accumulation of slower migrating phosphatase-sensitive forms indicates that its presence facilitates phosphorylation. In normal lung cells the serine variant is slightly more potent in inhibiting proliferation and migration. Additionally non-malignant cells expressing the major Sprouty2 variant attach more effective to fibronectin, while the serine variant only weakly stimulates cell adhesion. Mechanistically, the serine variant interferes less effectively with mitogen-activated protein kinase induction in response to serum. Concerning the positive Sprouty2 effect on epidermal growth factor receptor activation the serine variant is more potent. In all lung cancer-derived cell lines proliferation is more effectively inhibited if the Sprouty2 protein harbours the serine. In contrast, an increased interference of the serine Sprouty2 variant is only observed in cells with unaltered K-Ras. In cells harbouring a K-Ras mutation the serine conversion weakens the reduction of migration velocity indicating that dependent on the status of K-Ras the serine influences Sprouty2 functions differently. Accordingly, cell adhesion in cells with unaffected K-Ras is only stimulated by a Sprouty2 protein harbouring proline, while a serine conversion improves the attachment of the cells with constitutive active Ras. In summary our studies demonstrate that substitution of proline by serine at position 106 has biological significance and that the observed effects of this conversion depend on the activation status of endogenous K-Ras. J. Cell. Biochem. 117: 1822-1832, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Rosana
authors.initials: R
authors.lastname: Kral
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Angelina
authors.initials: A
authors.lastname: Doriguzzi
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Christoph-Erik
authors.initials: CE
authors.lastname: Mayer
authors.affiliation: Institute for Pathology and Bacteriology, Otto Wagner Hospital, Baumgartner Höhe, A-1140 Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Krenbek
authors.affiliation: Institute for Pathology and Bacteriology, Otto Wagner Hospital, Baumgartner Höhe, A-1140 Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Setinek
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Hedwig
authors.initials: H
authors.lastname: Sutterlüty-Fall
mesh_terms: D000072283:A549 Cells; D003062:Codon / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism
chemical_list: D003062:Codon; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D008565:Membrane Proteins; C485561:SPRY2 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CELL ADHESION; CELL MOVEMENT; CELL PROLIFERATION; K-Ras MUTATION; LUNG NEOPLASMS; MITOGEN-ACTIVATED PROTEIN KINASES; SPROUTY