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Constitutive activation of oncogenic PDGFR-mutants found in GIST patients induces receptor mislocalisation and alters PDGFR-A signalling characteristics

ABSTRACT: Gastrointestinal stomal tumors (GIST) are mainly characterised by the presence of activating mutations in either of the two receptor tyrosine kinases c-KIT and Platelet-derived growth factor receptor-a (PDGFRa). Most mechanistic studies dealing with GIST mutations have focused on c-KIT and far less is known about the signalling characteristics of the mutated PDGFRa proteins. Comparative studies of the signal transduction capacities of different mutant proteins cannot be performed in patient cells due to the patient specific background which may influence the signalling behaviour of the investigated mutants. In addition, the lack of a real wild-type signalling control (PDGFRa-WT) hampers comparisons of the signalling of wild-type and mutant proteins. Therefore, we stably and inducibly expressed different PDGFRa mutants as well as wild-type PDGFRa on an isogenic background in 293T cells in order to study the signalling capacities and corresponding transcriptional responses of the different proteins. We found that the constitutive signalling via the oncogenic PDGFRa 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 PDGFRa mutants is not solely characterised by a constitutive activation of the conventional PDGFRa signalling pathways.

ORGANISM(S): Homo sapiens

SUBMITTER: Arnaud Muller

PROVIDER: E-MTAB-2101 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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