Critical Role of the Platelet-derived Growth Factor Receptor (PDGFR) β Transmembrane Domain in the TEL-PDGFRβ Cytosolic Oncoprotein

The fusion of TEL with platelet-derived growth factor receptor (PDGFR) beta (TP beta) is found in a subset of patients with atypical myeloid neoplasms associated with eosinophilia and is the archetype of a larger group of hybrid receptors that are produced by rearrangements of PDGFR genes. TP beta is activated by oligomerization mediated by the pointed domain of TEL/ETV6, leading to constitutive activation of the PDGFR beta kinase domain. The receptor transmembrane (TM) domain is retained in TP beta and in most of the described PDGFR beta hybrids. Deletion of the TM domain (Delta TM-TP beta) strongly impaired the ability of TP beta to sustain growth factor-independent cell proliferation. We confirmed that TP beta resides in the cytosol, indicating that the PDGFR beta TM domain does not act as a transmembrane domain in the context of the hybrid receptor but has a completely different function. The Delta TM-TP beta protein was expressed at a lower level because of increased degradation. It could form oligomers, was phosphorylated at a slightly higher level, co-immunoprecipitated with the p85 adaptor protein, but showed a much reduced capacity to activate STAT5 and ERK1/2 in Ba/F3 cells, compared with TP beta. Inanin vitro kinase assay, Delta TM-TP beta was more active than TP beta and less sensitive to imatinib, a PDGFR inhibitor. In conclusion, we show that the TM domain is required for TP beta-mediated signaling and proliferation, suggesting that the activation of the PDGFR beta kinase domain is not enough for cell transformation.