Cell Biology/ Signal Transduction

M. Muller, J. Briscoe, C. Laxton, D. Guschin, A. Ziemiecki, O. Silvennoinen, A.G. Harpur, G. Barblerl, B.A. Witthuhn, C. Schindler, S. Pellegrini, A.F. Wilks, J.N. Ihle, G. Stark, I.M. Kerr, "The protein tyrosine kinase JAK1 complements defects in interferon-a/b and g signal transduction," Nature, 366:129-35, 1993. (Cited in more than 150 publications through September 1995) Z. Zhong, Z.L. Wen, J.E. Darnell, Jr., "STAT3-a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6," Science, 264:95-8, 1994. (Cited in about 100 publications through September 1995) Comments by James E. Darnell, Jr., Rockefeller University; George R. Stark, Cleveland Clinic Foundation Research Institute; and Zhong Zhong, Columbia University College of Physicians and Surgeons These papers are two among a host of highly cited reports on the subject of signal transduction involving two protein families-the JAKs and STATs-to emerge from the laboratories of James E. Darnell, Jr. at Rockefeller University, Ian M. Kerr of the Imperial Cancer Research Fund in London, and George R. Stark of the Cleveland Clinic Foundation Research Institute. They represent two independent approaches-genetic and biochemical-to studying various aspects of the signaling system. 'JAKS' OF ALL TRADES: James E. Darnell, left and Zhong Zhong discovered the ubiquity of the JAK-STAT pathway of signal transduction. According to Darnell, head of the laboratory of molecular cell biology at Rockefeller University, the widespread interest in these papers in the scientific community reflects the participation of the JAK and STAT proteins in the direct activation of genes in the nucleus of the cell in response to protein fragments binding to the surface. "When we first started studying these proteins, our main goal was to determine how interferon signaling worked," comments Stark, chairman of the Cleveland Clinic Foundation Research Institute. At the time that the proteins were first isolated, he asserts, "no one had any clue that they were part of a much more generalized mechanism of transmitting signals" in cells. The JAKs, explains Stark, are members of a "family of tyrosine kinases that were originally cloned by their homology to other tyrosine kinases, but without any idea as to what their function might be." Tyrosine kinases are a group of enzymes that activate various intracellular proteins by transferring phosphate groups to amino acids called tyrosines of these proteins, in response to signals from outside the cell. The initial lack of information about the JAKs is reflected in the name; JAK is an acronym for "just another kinase," remarks Stark. Meanwhile, the STAT proteins were discovered by Darnell's laboratory using a biochemical approach, as the transcription factors that were activated in response to signals from interferon-a (C. Schindler et al., Proceedings of the National Academy of Sciences, 89:7836-9, 1992; X.-Y. Fu et al., PNAS, 89:7840-3, 1992; C. Schindler et al., Science, 257:809-13, 1992). Their name, which is an acronym for "signal transducers and activators of transcription," was also chosen by James Darnell "as a deliberate pun on the medical term 'stat,' which means 'instantly,' because the STATs showed an immediate and direct response to the binding of [interferon] to the cell-surface receptor," Stark relates. In their article (M. Muller et al., Nature, 366:129-35, 1993), Stark, Kerr, and colleagues demonstrated the function of the JAK1 protein in the cellular responses to two different types of interferon signaling. COMPLEMENTATION: Using genetic techniques, George R. Stark, left, and Ian M. Kerr demonstrated the precise role of JAK1 in interferon signaling. "The main contribution of this paper is that it complemented Darnell's biochemical approach with mutation analysis to define the various steps in interferon signaling," explains Stark. "For the first time, we were successful in applying the methods of mutagenesis and gene complementation-a tried-and-true method in haploid organisms-to diploid, mammalian cells. "Our key observation was that JAK1 could compensate for the defects in signal transduction in response to both the a/b-type, as well as g-interferons." This finding established the requirement for the protein in signal transduction. Putting together this and other mutation analyses "begins to get at some of the reasons for why and how different kinases are used in a given pathway," Stark adds. Zhong Zhong, currently a postdoctoral fellow at the Columbia University College of Physicians and Surgeons, as a graduate student in Darnell's laboratory, discovered the first STATs to be activated by polypeptides other than interferon. Zhong says that the significance of their work is that it shows the existence of "a large gene family that is heavily used for gene regulation by a number of cytokines and growth factors." For instance, one of the papers to emerge from Darnell's laboratory identified and sequenced two members of the STAT family (Z. Zhong et al., PNAS, 91:4806-10, 1994). In their 1994 Science paper, the researchers showed that one of these-STAT3-could be activated by epidermal growth factors and interleukin-6. The articles listed here, all less than two years old, have received a substantially greater number of citations than others of the same type and vintage, according to data from the Science Citation Index( of the Institute for Scientific Information, Philadelphia. Why have these research reports become such standouts? In conversations with The Scientist, the authors attempt to provide an answer. (The Scientist, Vol:9, #19, pg.15 , October 2, 1995) (Copyright © The Scientist, Inc.)

Cell Biology/ Signal Transduction

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