title: The tyrosine phosphatase SHP2 is required for cell transformation by the receptor tyrosine kinase mutants FIP1L1-PDGFRα and PDGFRα D842V.
abstract: Activated forms of the platelet derived growth factor receptor alpha (PDGFRα) have been described in various tumors, including FIP1L1-PDGFRα in patients with myeloproliferative diseases associated with hypereosinophilia and the PDGFRα(D842V) mutant in gastrointestinal stromal tumors and inflammatory fibroid polyps. To gain a better insight into the signal transduction mechanisms of PDGFRα oncogenes, we mutated twelve potentially phosphorylated tyrosine residues of FIP1L1-PDGFRα and identified three mutations that affected cell proliferation. In particular, mutation of tyrosine 720 in FIP1L1-PDGFRα or PDGFRα(D842V) inhibited cell growth and blocked ERK signaling in Ba/F3 cells. This mutation also decreased myeloproliferation in transplanted mice and the proliferation of human CD34(+) hematopoietic progenitors transduced with FIP1L1-PDGFRα. We showed that the non-receptor protein tyrosine phosphatase SHP2 bound directly to tyrosine 720 of FIP1L1-PDGFRα. SHP2 knock-down decreased proliferation of Ba/F3 cells transformed with FIP1L1-PDGFRα and PDGFRα(D842V) and affected ERK signaling, but not STAT5 phosphorylation. Remarkably, SHP2 was not essential for cell proliferation and ERK phosphorylation induced by the wild-type PDGF receptor in response to ligand stimulation, suggesting a shift in the function of SHP2 downstream of oncogenic receptors. In conclusion, our results indicate that SHP2 is required for cell transformation and ERK activation by mutant PDGF receptors.
authors.affiliation: de Duve Institute, Université catholique de Louvain, MEXP - UCL B1.74.05, Avenue Hippocrate 75, BE-1200 Brussels, Belgium. Electronic address: laura.noel@uclouvain.be.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Noël
authors.affiliation: de Duve Institute, Université catholique de Louvain, MEXP - UCL B1.74.05, Avenue Hippocrate 75, BE-1200 Brussels, Belgium. Electronic address: florence.arts@uclouvain.be.
authors.forename: Florence A
authors.initials: FA
authors.lastname: Arts
authors.affiliation: de Duve Institute, Université catholique de Louvain, MEXP - UCL B1.74.05, Avenue Hippocrate 75, BE-1200 Brussels, Belgium. Electronic address: carmen.patricia.montano@gmail.com.
authors.forename: Carmen P
authors.initials: CP
authors.lastname: Montano-Almendras
authors.affiliation: Center for The Biology of Disease, VIB, Herestraat 49, BE-3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, Leuven, Belgium. Electronic address: Luk.Cox@cme.vib-kuleuven.be.
authors.forename: Luk
authors.initials: L
authors.lastname: Cox
authors.affiliation: Center for The Biology of Disease, VIB, Herestraat 49, BE-3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, Leuven, Belgium. Electronic address: Olga.Gielen@cme.vib-kuleuven.be.
authors.forename: Olga
authors.initials: O
authors.lastname: Gielen
authors.affiliation: de Duve Institute, Université catholique de Louvain, MEXP - UCL B1.74.05, Avenue Hippocrate 75, BE-1200 Brussels, Belgium. Electronic address: federica.toffalini@gmail.com.
authors.forename: Federica
authors.initials: F
authors.lastname: Toffalini
authors.affiliation: de Duve Institute, Université catholique de Louvain, MEXP - UCL B1.74.05, Avenue Hippocrate 75, BE-1200 Brussels, Belgium. Electronic address: catherine.marbehant@gmail.com.
authors.forename: Catherine Y
authors.initials: CY
authors.lastname: Marbehant
authors.affiliation: Center for The Biology of Disease, VIB, Herestraat 49, BE-3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, Leuven, Belgium. Electronic address: jan.cools@cme.vib-kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.affiliation: de Duve Institute, Université catholique de Louvain, MEXP - UCL B1.74.05, Avenue Hippocrate 75, BE-1200 Brussels, Belgium. Electronic address: jb.demoulin@uclouvain.be.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; D050799:STAT5 Transcription Factor; D039221:mRNA Cleavage and Polyadenylation Factors; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Chronic eosinophilic leukemia; PDGFRA; PTPN11; SHP2; STAT5