Reference : Constitutive activation of oncogenic PDGFRalpha-mutant proteins occurring in GIST pat...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
Human health sciences : Oncology
http://hdl.handle.net/10993/21563
Constitutive activation of oncogenic PDGFRalpha-mutant proteins occurring in GIST patients induces receptor mislocalisation and alters PDGFRalpha signalling characteristics.
English
Bahlawane, Christelle mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Eulenfeld, Rene [> >]
Wiesinger, Monique mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Wang, Jiali mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Muller, Arnaud [> >]
Girod, Andreas mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Nazarov, Petr V. [> >]
Felsch, Kathrin [> >]
Vallar, Laurent [> >]
Sauter, Thomas mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
Satagopam, Venkata mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Haan, Serge mailto [University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit]
2015
Cell Communication and Signaling
13
21
Yes
International
1478-811X
1478-811X
England
[en] BACKGROUND: Gastrointestinal stromal tumours (GIST) are mainly characterised by the presence of activating mutations in either of the two receptor tyrosine kinases c-KIT or platelet-derived growth factor receptor-alpha (PDGFRalpha). Most mechanistic studies dealing with GIST mutations have focused on c-KIT and far less is known about the signalling characteristics of the mutated PDGFRalpha proteins. Here, we study the signalling capacities and corresponding transcriptional responses of the different PDGFRalpha proteins under comparable genomic conditions. RESULTS: We demonstrate that the constitutive signalling via the oncogenic PDGFRalpha mutants favours a mislocalisation of the receptors and that this modifies the signalling characteristics of the mutated receptors. We show that signalling via the oncogenic PDGFRalpha mutants is not solely characterised by a constitutive activation of the conventional PDGFRalpha signalling pathways. In contrast to wild-type PDGFRalpha signal transduction, the activation of STAT factors (STAT1, STAT3 and STAT5) is an integral part of signalling mediated via mutated PDGF-receptors. Furthermore, this unconventional STAT activation by mutated PDGFRalpha is already initiated in the endoplasmic reticulum whereas the conventional signalling pathways rather require cell surface expression of the receptor. Finally, we demonstrate that the activation of STAT factors also translates into a biologic response as highlighted by the induction of STAT target genes. CONCLUSION: We show that the overall oncogenic response is the result of different signatures emanating from different cellular compartments. Furthermore, STAT mediated responses are an integral part of mutated PDGFRalpha signalling.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
University of Luxembourg - UL
http://hdl.handle.net/10993/21563
10.1186/s12964-015-0096-8
http://www.biosignaling.com/content/13/1/21
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

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