TEL-JAK2 mediates constitutive activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway

A subset of chromosomal translocations that participate in leukemia involve activated tyrosine kinases. The ets transcription factor, TEL, undergoes t ranslocations with several distinct tyrosine kinases including JAK2. TEL-JA K2 transforms cell lines to factor independence, and constitutive tyrosine kinase activity results in the phosphorylation of several substrates includ ing STAT1, STAT3, and STAT5. In this study we have shown that TEL-JAK2 can constitutively activate the phosphatidylinositol 3'-kinase (PI 3'-kinase) s ignaling pathway. The regulatory subunit of PI 3'-kinase, p85, associates w ith TEL-JAK2 in immunoprecipitations, and this was shown to be mediated by the amino-terminal SH2 domain of p85 but independent of a putative p85-bind ing motif within TEL-JAK2. The scaffolding protein Gab2 can also mediate th e association of p85. TEL-JAK2 constitutively phosphorylates the downstream substrate protein kinase B/AKT. Importantly, the pharmacologic PI 3'-kinas e inhibitor, LY294002, blocked TEL-JAK2 factor-independent growth and phosp horylation of protein kinase B. However, LY294002 did not alter STAT5 tyros ine phosphorylation, indicating that STAT5 and protein kinase B activation mediated by TEL-JAK2 are independent signaling pathways. Therefore, activat ion of the PI 3'-kinase signaling pathway is an important event mediated by TEL-JAK2 chromosomal translocations.