Janus kinases and their role in growth and disease

Janus kinases (JAK) play a crucial role in the initial steps of cytokine si gnaling. Each of the four members (JAK1, JAK2, JAK3, TYK2) of this non-rece ptor tyrosine kinase family is indispensable for the effects of distinct cy tokines. Moreover, recent reports have added to our knowledge on their high ly specific functions: JAK3 knockout mice and JAK3 deficient patients canno t signal through the interleukin-2,4,7,9, or 15 receptors and suffer from s evere combined immunodeficiency (SCID). JAK1 and JAK2 knockout mice do not survive, their cells again showing distinct patterns of cytokine signaling deficits. At the other end of the spectrum, JAK fusion proteins have been s hown to play a role in leukemias. In addition, a new class of JAK-specific inhibitors was described by several groups, the CIS/SOCS/Jab family. This r eview on the rapidly growing field focuses on JAK function and regulation, and on their emerging role in development and human disease.