Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes.

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 Cell

journal_title

Molecular cell

authors

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 H

doi

10.1016/j.molcel.2009.09.019

subject

Has Abstract

pub_date

2009-10-23 00:00:00

pages

326-39

issue

2

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(09)00677-7

journal_volume

36

pub_type

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