Signal transduction by PDGF receptor mutants in hematopoietic neoplasms
(2014)
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Details
- Authors
- Supervisors
- Demoulin, Jean-Baptiste
- Abstract
- Activated forms of the platelet-derived growth factor receptor (PDGFR) have been described in various cancers. We studied three of them: FIP1L1-PDGFRα (FPα) and KANK1-PDGFRβ (KPβ), which are detected in patients with myeloproliferative diseases, associated with hypereosinophilia or thrombocythemia, respectively and the PDGFRA D842V mutant in gastrointestinal tumors. The aim of the work was to gain a better insight into the signal transduction mechanisms of PDGFR oncogenes. The Ba/F3 cell line is a common model used to study PDGFR mutants. Additional experiments were performed in vivo in BALB/c mice and in a more physiological model, the human CD34+ hematopoietic progenitors and stem cells, which were isolated from human cord blood. In a first study, we observed that KPβ constitutively activated the STAT5 transcription factors, but this did not require JAK kinases. In addition, KPβ induced the phosphorylation of phospholipase Cγ and ERK1/2. We next tested the impact of various mutant forms of KPβ for Ba/F3 and CD34+ cell transformation. The three coiled-coil domains located in the N-terminus of KANK1 were required for KPβ-induced cell growth and signaling via STAT5 and ERK1/2. However, these three domains are not essential for KPβ oligomerization. KPβ is the first example of thrombocythemia-associated oncogene that does not signal via JAK2. In a second study, we mutated each of the twelve potentially phosphorylated tyrosine residues of FPα. Mutation of tyrosine 720 in FPα or PDGFRAD842V inhibited cell growth and blocked ERK1/2 signaling in Ba/F3 cells. This mutation also decreased myeloproliferation in transplanted mice and the proliferation of CD34+ cells transduced with FPα. Since the non-receptor protein tyrosine phosphatase SHP2 is known to bind to tyrosine 720 in wild-type PDGFRα, we evaluated its role downstream from FPα and PDGFRAD842V. We found that SHP2 knock-down decreased proliferation and ERK1/2 signaling, but not STAT5 phosphorylation in transformed Ba/F3 cells. However, SHP2 was not essential for cell proliferation and ERK1/2 phosphorylation induced by the wild-type PDGF receptor in response to ligand stimulation. In conclusion, our results indicate that the malignant transformation by receptor tyrosine kinase mutants require the activation of different signaling pathways. Interestingly, signal transduction downstream from receptor tyrosine kinase oncogenes can be altered compared with the wild-type receptor.
- Affiliations
Citations
Noël, L. (2014). Signal transduction by PDGF receptor mutants in hematopoietic neoplasms. https://hdl.handle.net/2078.5/48235