JAK2 IS ESSENTIAL FOR SIGNALING THROUGH A VARIETY OF CYTOKINE RECEPTORS

A variety of cytokines activate receptor-associated members of the Jan us family of protein tyrosine kinases (Jaks). To assess the role of Ja k2, we have derived Jak2-deficient mice. The mutation causes an embryo nic lethality due to the absence of definitive erythropoiesis. Fetal l iver myeloid progenitors, although present based on the expression of lineage specific markers, fail to respond to erythropoietin, thrombopo ietin, interleukin-3 (IL-3), or granulocyte/macrophage colony-stimulat ing factor. In contrast, the response to granulocyte specific colony-s timulating factor is unaffected. Jak2-deficient fibroblasts failed to respond to interferon gamma (IFN gamma), although the responses to IFN alpha/beta and IL-6 were unaffected. Lastly, reconstitution experimen ts demonstrate that Jak2 is not required for the generation of lymphoi d progenitors, their amplification, or functional differentiation. The refore, Jak2 plays a critical, nonredundant role in the function of a specific group of cytokines receptors.