TEL-JAK2 constitutively activates the extracellular signal–regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways

• Published in: Blood Vol. 100; no. 4; pp. 1438 - 1448
• Main Authors: Ho, Jenny M.-Y., Nguyen, Melody H.-H., Dierov, Jamil K., Badger, Karla M., Beattie, Bryan K., Tartaro, Piero, Haq, Rizwan, Zanke, Brent W., Carroll, Martin P., Barber, Dwayne L.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-08-2002; The Americain Society of Hematology
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Biological and medical sciences; Cell Line; Enzyme Activation; GRB2 Adaptor Protein; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mitogen-Activated Protein Kinase 8; Mitogen-Activated Protein Kinases - metabolism; Mutation; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - physiology; p38 Mitogen-Activated Protein Kinases; Phenylalanine; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Phosphotyrosine - metabolism; Proteins - metabolism; ras Proteins - metabolism; Shc Signaling Adaptor Proteins; Signal Transduction; Src Homology 2 Domain-Containing, Transforming Protein 1; Tyrosine; Human; Signal transduction; Extracellular signal-regulated protein kinase; Enzyme; Pathogenesis; Transferases; Established cell line; Gene rearrangement; Mitogen-activated protein kinase; Malignant hemopathy; Carcinogenesis; Protein-tyrosine kinase
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V100.4.1438.h81602001438_1438_1448

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.