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Cell Commun Signal. 2015 Mar 31;13:21. doi: 10.1186/s12964-015-0096-8.

Constitutive activation of oncogenic PDGFRα-mutant proteins occurring in GIST patients induces receptor mislocalisation and alters PDGFRα signalling characteristics.

Author information

1
Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. christelle.bahlawane@uni.lu.
2
Signal Transduction Group, Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. r_eule@gmx.de.
3
Systems Biology Group, Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. monique.wiesinger@uni.lu.
4
Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. jiali.wang@uni.lu.
5
Genomics Research Unit, Luxembourg Institute of Health, 84 Val Fleuri, L-1526, Luxembourg, Luxembourg. Arnaud.Muller@lih.lu.
6
Light Microscopy Facility, Life Sciences Research Unit, University of Luxembourg, 162a Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. andreas.girod@uni.lu.
7
Genomics Research Unit, Luxembourg Institute of Health, 84 Val Fleuri, L-1526, Luxembourg, Luxembourg. Petr.Nazarov@lih.lu.
8
Deparment of Biochemistry, RWTH-Aachen University, Pauwelsstr. 30, D-52074, Aachen, Germany. Kathrin.Felsch@gmx.de.
9
Genomics Research Unit, Luxembourg Institute of Health, 84 Val Fleuri, L-1526, Luxembourg, Luxembourg. Laurent.Vallar@lih.lu.
10
Systems Biology Group, Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. thomas.sauter@uni.lu.
11
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts-Fourneaux, L-4362, Esch-sur-Alzette, Luxembourg. venkata.satagopam@uni.lu.
12
Molecular Disease Mechanisms Group, Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. serge.haan@uni.lu.
13
Signal Transduction Group, Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faïencerie, L-1511, Luxembourg, Luxembourg. serge.haan@uni.lu.
14
Deparment of Biochemistry, RWTH-Aachen University, Pauwelsstr. 30, D-52074, Aachen, Germany. serge.haan@uni.lu.

Abstract

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-α (PDGFRα). Most mechanistic studies dealing with GIST mutations have focused on c-KIT and far less is known about the signalling characteristics of the mutated PDGFRα proteins. Here, we study the signalling capacities and corresponding transcriptional responses of the different PDGFRα proteins under comparable genomic conditions.

RESULTS:

We demonstrate that the constitutive signalling via the oncogenic PDGFRα 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 PDGFRα mutants is not solely characterised by a constitutive activation of the conventional PDGFRα signalling pathways. In contrast to wild-type PDGFRα 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 PDGFRα 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 PDGFRα signalling.

PMID:
25880691
PMCID:
PMC4396151
DOI:
10.1186/s12964-015-0096-8
[Indexed for MEDLINE]
Free PMC Article

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