Transcription profiling by array of human HEK-293 cells transfected with inducible wild-type PDFGRa or oncogenic FIP1L1-PDGFRa fusion proteins (cytoplasmic or membrane-localised) as models to study transcriptional and signalling characteristics of the fusion protein in human cancers

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-PDGFRa kinase exhibits a significantly different signaling pattern compared to PDGFRa wildtype: Interestingly, the conventional strong activation of PI3-kinase- and MAP-kinase- pathways is remarkably shifted towards a prominent activation of STAT factors. This diverging signaling pattern compared to classical PDGF-receptor signaling is partially coupled to the aberrant intracellular location of the oncogene, since membrane targeting of F/PDGFRa restores activation of MAPK- and PI3K-pathway completely. In contrast to the “classical” cytokine-induced STAT-activation process does STAT activation by F/PDGFR not require Janus kinase activity and does not involve a SH2-domain-mediated binding mechanism. Thus it is conceivable that STAT activation by F/PDGFR could be directly mediated by interaction of STAT factors with the kinase domain itself.