title: TEL-JAK2 constitutively activates the extracellular signal-regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways.
abstract: The ets transcription factor, TEL, undergoes chromosomal rearrangements with the tyrosine kinase JAK2. TEL-JAK2 is constitutively active, confers cell line factor independence, and activates signal transducer and activator of transcription-1 (STAT1), STAT3, and STAT5. Data from bone marrow transplantation models suggest that STAT5 activation does not account for the entire disease phenotype induced by TEL-JAK2. This study examined additional signaling pathways that are activated by TEL-JAK2. TEL-JAK2 expression in Ba/F3 cells results in constitutive association and tyrosine phosphorylation of Shc and Ship-1 and, consequently, recruitment of Grb2 to TEL-JAK2. Direct Grb2 recruitment is also possible because a putative Grb2 binding site, Tyr314, is present on TEL-JAK2(5-19) and TEL-JAK2(5-12). Studies with a TEL-JAK2(5-19)Tyr314Phe mutant support a role for Tyr314 in Grb2 recruitment, because Grb2 association with TEL-JAK2(5-19)Tyr314Phe is significantly reduced. Interestingly, TEL-JAK2(5-19)Tyr314Phe shows reduced Ras activation when compared with TEL-JAK2(4-17), TEL-JAK2(5-12), and TEL-JAK2(5-19). Analysis of extracellular signal-regulated kinase-1/2 (ERK1/2), stress-activated protein/Jun kinase (SAPK/JNK), and p38 demonstrates the activation of SAPK/JNK and phosphorylation of p38 by all TEL-JAK2 isoforms. TEL-JAK2(5-12) and TEL-JAK2(5-19) preferentially phosphorylate ERK2, whereas TEL-JAK2(4-17) phosphorylated ERK2 at lower levels. Inhibition studies demonstrated that ERK1/2 activation was necessary for Ba/F3 factor independence mediated by TEL-JAK2(5-19), while inhibition of SAPK/JNK or p38 activity had no effect. Our data reveal the requirement of ERK activation by TEL-JAK2(5-19) in Ba/F3 cells and suggest that TEL-JAK2 leukemogenic potential may be mediated in part through ERK1/2.
authors.affiliation: Division of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, University of Toronto, Ontario, Canada.
authors.forename: Jenny M-Y
authors.initials: JM
authors.lastname: Ho
authors.forename: Melody H-H
authors.initials: MH
authors.lastname: Nguyen
authors.forename: Jamil K
authors.initials: JK
authors.lastname: Dierov
authors.forename: Karla M
authors.initials: KM
authors.lastname: Badger
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Beattie
authors.forename: Piero
authors.initials: P
authors.lastname: Tartaro
authors.forename: Rizwan
authors.initials: R
authors.lastname: Haq
authors.forename: Brent W
authors.initials: BW
authors.lastname: Zanke
authors.forename: Martin P
authors.initials: MP
authors.lastname: Carroll
authors.forename: Dwayne L
authors.initials: DL
authors.lastname: Barber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D010649:Phenylalanine; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D015514:Oncogene Proteins, Fusion; D010649:Phenylalanine; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases; D019000:Phosphotyrosine; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; C495949:Grb2 protein, mouse; C528034:Shc1 protein, mouse; C108603:TEL-JAK2 fusion protein, human; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein; C491568:TEL-JAK2 fusion protein, mouse; C098706:INPPL1 protein, human