c-Abl activates Janus kinase 2 in normal hematopoietic cells [Molecular Bases of Disease]

June 12th, 2014 by Tao, W., Leng, X., Chakraborty, S. N., Ma, H., Arlinghaus, R. B.

Jak2 is involved in cytokine growth factor stimulated signal transduction but the mechanism of its activation is largely unknown. Here, we investigated Jak2 activation in a normal hematopoietic cell line, 32D mouse myeloid cells. The BiFC studies showed that c-Abl formed a stable complex with Jak2 in live cells. Co-IP results showed that c-Abl bound to βc chain of IL-3/IL-5/GM-CSF receptors. The kinase activities of both c-Abl and Jak2 were stimulated by IL-3 in 32D cells. Decreasing c-Abl protein expression in 32D cells by inducible shRNA decreased Jak2 activity and resulted in the failure of Jak2 activation in response to IL-3. Treatment of IL-3 and serum-starved 32D cells with 1 μM IM inhibited IL-3 stimulated kinase activities of both c-Abl and Jak2. In addition, the kinase-deficient Bcr-Abl mutant (p210K1172R) was defective for activation of Jak2 in 32D cells and impaired IL-3 independent growth, which was rescued by overexpression of c-Abl (+Abl). IL-3 efficiently inhibited apoptosis of 32Dp210K/R+Abl cells induced by IM but not Jak2 kinase inhibitor TG101209. In summary, our findings provide evidence that the kinase function of c-Abl and its C-terminal CT-4 region are crucial for its interaction with Jak2 and its activation. c-Abl kinase activity induced by IL-3 is required for IL-3 stimulated Jak2 activation. Our findings reveal a novel regulatory role of c-Abl in Jak2 activation induced by IL-3 cytokine growth factor in 32D hematopoietic cells.