Article (Scientific journals)
Constitutive activation of oncogenic PDGFRalpha-mutant proteins occurring in GIST patients induces receptor mislocalisation and alters PDGFRalpha signalling characteristics.
Bahlawane, Christelle; Eulenfeld, Rene; Wiesinger, Monique et al.
2015In Cell Communication and Signaling, 13, p. 21
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Abstract :
[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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Biochemistry, biophysics & molecular biology
Oncology
Author, co-author :
Bahlawane, Christelle ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Eulenfeld, Rene
Wiesinger, Monique ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Wang, Jiali ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Muller, Arnaud
Girod, Andreas ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Nazarov, Petr V.
Felsch, Kathrin
Vallar, Laurent
Sauter, Thomas ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Satagopam, Venkata ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Haan, Serge ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
External co-authors :
yes
Language :
English
Title :
Constitutive activation of oncogenic PDGFRalpha-mutant proteins occurring in GIST patients induces receptor mislocalisation and alters PDGFRalpha signalling characteristics.
Publication date :
2015
Journal title :
Cell Communication and Signaling
ISSN :
1478-811X
Publisher :
BioMed Central, London, United Kingdom
Volume :
13
Pages :
21
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
R-AGR-0085 - IRP11 - PDGFR-KIT (20110101-20141231) - HAAN Serge
Funders :
University of Luxembourg - UL
Available on ORBilu :
since 18 July 2015

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