TEL-JAK2 constitutively activates the extracellular signal-regulated kinase (ERK), stress-activated protein/Jun kinase (SAPK/JNK), and p38 signaling pathways.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Cell Line, Enzyme Activation, GRB2 Adaptor Protein, Mice, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinases, Mutation, Oncogene Proteins, Fusion, Phenylalanine, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphotyrosine, Proteins, Shc Signaling Adaptor Proteins, Signal Transduction, Src Homology 2 Domain-Containing, Transforming Protein 1, Tyrosine, p38 Mitogen-Activated Protein Kinases, ras Proteins
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Animals, Cell Line, Enzyme Activation, GRB2 Adaptor Protein, Mice, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinases, Mutation, Oncogene Proteins, Fusion, Phenylalanine, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Phosphorylation, Phosphotyrosine, Proteins, Shc Signaling Adaptor Proteins, Signal Transduction, Src Homology 2 Domain-Containing, Transforming Protein 1, Tyrosine, p38 Mitogen-Activated Protein Kinases, ras Proteins
Blood
Date: Aug. 15, 2002
PubMed ID: 12149229
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