Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes

Research output: Contribution to journalJournal articleResearchpeer-review

Chuna Ram Choudhary, Jesper V Olsen, Christian Brandts, Jürgen Cox, Pavankumar N G Reddy, Frank D Böhmer, Volker Gerke, Dirk-E Schmidt-Arras, Wolfgang E Berdel, Carsten Müller-Tidow, Matthias Mann, Hubert Serve

Inappropriate activation of oncogenic kinases at intracellular locations is frequently observed in human cancers, but its effects on global signaling are incompletely understood. Here, we show that the oncogenic mutant of Flt3 (Flt3-ITD), when localized at the endoplasmic reticulum (ER), aberrantly activates STAT5 and upregulates its targets, Pim-1/2, but fails to activate PI3K and MAPK signaling. Conversely, membrane targeting of Flt3-ITD strongly activates the MAPK and PI3K pathways, with diminished phosphorylation of STAT5. Global phosphoproteomics quantified 12,186 phosphorylation sites, confirmed compartment-dependent activation of these pathways and discovered many additional components of Flt3-ITD signaling. The differential activation of Akt and Pim kinases by ER-retained Flt3-ITD helped to identify their putative targets. Surprisingly, we find spatial regulation of tyrosine phosphorylation patterns of the receptor itself. Thus, intracellular activation of RTKs by oncogenic mutations in the biosynthetic route may exploit cellular architecture to initiate aberrant signaling cascades, thus evading negative regulation.
Original languageEnglish
JournalMolecular Cell
Volume36
Issue number2
Pages (from-to)326-39
Number of pages13
ISSN1097-2765
DOIs
Publication statusPublished - 2009

ID: 16275216