Abstract:
: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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Choudhary C,Olsen JV,Brandts C,Cox J,Reddy PN,Böhmer FD,Gerke V,Schmidt-Arras DE,Berdel WE,Müller-Tidow C,Mann M,Serve Hdoi
10.1016/j.molcel.2009.09.019subject
Has Abstractpub_date
2009-10-23 00:00:00pages
326-39issue
2eissn
1097-2765issn
1097-4164pii
S1097-2765(09)00677-7journal_volume
36pub_type
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