title: The oncogenic FIP1L1-PDGFRα fusion protein displays skewed signaling properties compared to its wild-type PDGFRα counterpart.
abstract: Aberrant activation of oncogenic kinases is frequently observed in human cancers, but the underlying mechanism and resulting effects on global signaling are incompletely understood. Here, we demonstrate that the oncogenic FIP1L1-PDGFRα kinase exhibits a significantly different signaling pattern compared to its PDGFRα wild type counterpart. Interestingly, the activation of primarily membrane-based signal transduction processes (such as PI3-kinase- and MAP-kinase- pathways) is remarkably shifted toward a prominent activation of STAT factors. This diverging signaling pattern compared to classical PDGF-receptor signaling is partially coupled to the aberrant cytoplasmic localization of the oncogene, since membrane targeting of FIP1L1-PDGFRα restores activation of MAPK- and PI3K-pathways. In stark contrast to the classical cytokine-induced STAT activation process, STAT activation by FIP1L1-PDGFRα does neither require Janus kinase activity nor Src kinase activity. Furthermore, we investigated the mechanism of STAT5 activation via FIP1L1-PDGFRα in more detail and found that STAT5 activation does not involve an SH2-domain-mediated binding mechanism. We thus demonstrate that STAT5 activation occurs via a non-canonical activation mechanism in which STAT5 may be subject to a direct phosphorylation by FIP1L1-PDGFRα.
authors.affiliation: Molecular Disease Mechanisms Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: Serge
authors.initials: S
authors.lastname: Haan
authors.affiliation: Molecular Disease Mechanisms Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: Christelle
authors.initials: C
authors.lastname: Bahlawane
authors.affiliation: Molecular Disease Mechanisms Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: Jiali
authors.initials: J
authors.lastname: Wang
authors.affiliation: Genomics Research Unit; Luxembourg Institute of Health; Luxembourg , Luxembourg.
authors.forename: Petr V
authors.initials: PV
authors.lastname: Nazarov
authors.affiliation: Genomics Research Unit; Luxembourg Institute of Health; Luxembourg , Luxembourg.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Muller
authors.affiliation: Signal Transduction Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: René
authors.initials: R
authors.lastname: Eulenfeld
authors.affiliation: Signal Transduction Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: Claude
authors.initials: C
authors.lastname: Haan
authors.affiliation: Signal Transduction Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rolvering
authors.affiliation: Genomics Research Unit; Luxembourg Institute of Health; Luxembourg , Luxembourg.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.affiliation: Luxembourg Center for Systems Biomedicine; University of Luxembourg ; Esch-sur-Alzette, Luxembourg.
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Satagopam
authors.affiliation: Systems Biology Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sauter
authors.affiliation: Systems Biology Group; Life Sciences Research Unit; University of Luxembourg; Luxembourg , Luxembourg.
authors.forename: Monique Yvonne
authors.initials: MY
authors.lastname: Wiesinger
keywords: AKT; FIP1L1-PDGFRα; Janus kinase; MAP kinase; Platelet-derived growth factor; SH2-domain; STAT-factor; Src kinase