Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. / Choudhary, Chuna Ram; Olsen, Jesper V; Brandts, Christian; Cox, Jürgen; Reddy, Pavankumar N G; Böhmer, Frank D; Gerke, Volker; Schmidt-Arras, Dirk-E; Berdel, Wolfgang E; Müller-Tidow, Carsten; Mann, Matthias; Serve, Hubert.

In: Molecular Cell, Vol. 36, No. 2, 2009, p. 326-39.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Choudhary, CR, Olsen, JV, Brandts, C, Cox, J, Reddy, PNG, Böhmer, FD, Gerke, V, Schmidt-Arras, D-E, Berdel, WE, Müller-Tidow, C, Mann, M & Serve, H 2009, 'Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes', Molecular Cell, vol. 36, no. 2, pp. 326-39. https://doi.org/10.1016/j.molcel.2009.09.019

APA

Choudhary, C. R., Olsen, J. V., Brandts, C., Cox, J., Reddy, P. N. G., Böhmer, F. D., Gerke, V., Schmidt-Arras, D-E., Berdel, W. E., Müller-Tidow, C., Mann, M., & Serve, H. (2009). Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Molecular Cell, 36(2), 326-39. https://doi.org/10.1016/j.molcel.2009.09.019

Vancouver

Choudhary CR, Olsen JV, Brandts C, Cox J, Reddy PNG, Böhmer FD et al. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Molecular Cell. 2009;36(2):326-39. https://doi.org/10.1016/j.molcel.2009.09.019

Author

Choudhary, Chuna Ram ; Olsen, Jesper V ; Brandts, Christian ; Cox, Jürgen ; Reddy, Pavankumar N G ; Böhmer, Frank D ; Gerke, Volker ; Schmidt-Arras, Dirk-E ; Berdel, Wolfgang E ; Müller-Tidow, Carsten ; Mann, Matthias ; Serve, Hubert. / Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. In: Molecular Cell. 2009 ; Vol. 36, No. 2. pp. 326-39.

Bibtex

@article{bde84b60e97011deba73000ea68e967b,
title = "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.",
author = "Choudhary, {Chuna Ram} and Olsen, {Jesper V} and Christian Brandts and J{\"u}rgen Cox and Reddy, {Pavankumar N G} and B{\"o}hmer, {Frank D} and Volker Gerke and Dirk-E Schmidt-Arras and Berdel, {Wolfgang E} and Carsten M{\"u}ller-Tidow and Matthias Mann and Hubert Serve",
year = "2009",
doi = "10.1016/j.molcel.2009.09.019",
language = "English",
volume = "36",
pages = "326--39",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes

AU - Choudhary, Chuna Ram

AU - Olsen, Jesper V

AU - Brandts, Christian

AU - Cox, Jürgen

AU - Reddy, Pavankumar N G

AU - Böhmer, Frank D

AU - Gerke, Volker

AU - Schmidt-Arras, Dirk-E

AU - Berdel, Wolfgang E

AU - Müller-Tidow, Carsten

AU - Mann, Matthias

AU - Serve, Hubert

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2009.09.019

DO - 10.1016/j.molcel.2009.09.019

M3 - Journal article

C2 - 19854140

VL - 36

SP - 326

EP - 339

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 2

ER -

ID: 16275216