The JAK-STAT pathway at 20

On September 22–24, 2011 a group of over 150 scientists convened at the National Institutes of Health in Bethesda, Maryland to celebrate the 20th anniversary of the definitive molecular studies that revealed the JAK-STAT pathway. Organized chiefly by John O’Shea with a big assist from Richard Jove and minor assists from David Levy, myself and others, scientists from Europe, Asia, Australia, and, of course, the United States and Canada presented over 50 papers and 50 posters. The proteins in this pathway have proved to be pervasively important in normal cellular functions including infectious disease, immunology, inflammation and developmental biology. Moreover when the proteins are abnormally activated or mutated the pathway assumes great importance in human disease. Therefore it was certainly a propitious time for a celebratory conference. It was proudly noted and saluted that the group was not limited to academic scientists but included at least 15–20 scientists from the pharmaceutical world. This group reported promising advances in using information from basic studies to not only attempt drug development but at least in the case of JAK inhibitors to succeed in making promising pharmaceuticals. Reflecting on the success of this meeting it is certainly equally logical at this point in time to launch a new journal, JAK-STAT, aimed at comprehensive coverage of basic and clinical research that is arising and will continue to arise from further studies of the JAK-STAT pathway. Appropriately enough the enormous number of studies concerned with the cellular and organ function of each of the seven STATs and four JAKs make up a very large fraction of new results. Mouse strains with knockouts, total or cell specific, and mutant replacements of specific STATs and of elements that signal (activate) specific STATs are now standard fare. Because the molecules have such protean function the possible useful and enlightening experiments of this sort are virtually endless. Likewise on the functional biochemical side, the number of cooperating or inhibiting proteins affecting the pathway is already very large and continues to grow. For example, several revealing recent studies demonstrate functional STAT activation by tyrosine kinases other than JAKs. While a great deal has been learned about the structure of STATs, both activated and quiescent, all details that one could wish for are hardly known. This is particularly true at the structural level. For example, structure of the JAKs, especially in action while activating STATs, is not available. In general, co-crystals with important interacting proteins have not advanced very far. Suppose you wished to inhibit the entry of a specific STAT into the nucleus. There is, to my knowledge, no structure of an importin with a dimeric STAT and too little understanding of shuttling of the non-phosphorylated STATs into and out of the nucleus. On the clinical-pharmacologic side the opportunities are also, if not limitless, very great. JAK inhibitors are getting a good workout even now and their import on disease, especially cancer, with possibly autoimmune/allergic and inflammatory diseases to follow. STAT inhibitors (especially STAT3 and STAT5 that are persistently active in cancers, lymphomas and leukemias) are topics of intense interest and great practical importance. Finally, a mention should be made of cytokine mimics. For example, cancer therapy necessitates the use of several cytokines to support bone marrow function. All of these have been traditionally administered as proteins. Are small molecule mimics for each cytokine in our future? There will be no lack of interesting basic and clinically important discoveries in this broad field any of which should be comfortably included in this new journal. My expectation is, and I offer best wishes for, a rousing success!