Signal Transduction

Edited by: Karen Young Kreeger "Bloody Hot" Field: Because the signaling protein Stat5 has been found to be active in numerous pathways, many researchers are engaged in studying its various roles, says James Ihle. M. Azam, H. Erdjument-Bromage, B.L. Kreider, M. Xia, F. Quelle, R. Basu, C. Saris, P. Tempst, J.N. Ihle, C. Schindler, "Interleukin-3 signals through multiple isoforms of Stat5," EMBO Journal, 14:1402-11, 1995. (Cited in nearly 70 publications as of December 1996) Comments by James N. Ihle, St. Jude Children's Research Hospital, Memphis, Tenn. This paper describes one important piece of the overall picture of how cytokines orchestrate the immune response. "Four years ago, people had cloned many receptors for cytokines," says senior author James N. Ihle, chairman of the biochemistry department at St. Jude Children's Research Hospital in Memphis, Tenn. "What became obvious was that all of these cytokines used structurally related receptors and that these comprised a novel family of receptors. But no one knew how these receptors worked because the structure didn't give any hint." Three previous papers began to crystallize the notion that these receptors work by associating with one or more of the JAK tyrosine kinases, which are catalytic enzymes. The first linked JAKs to cytokine signaling (L. Velazquez et al., Cell, 70:313-22, 1992). The next two, published a year later by Ihle's group, pointed to a general role for the JAK molecules in cytokine signaling (L.S. Artgetsinger et al., Cell, 74:237-44, 1993; B. Witthuhn et al., Cell, 74:227-36, 1993). "What we proposed in the [1993 Witthuhn Cell] paper was that perhaps all of these cytokines will use members of the Stat protein-a signal-transducing factor-in a JAK-Stat pathway," recalls Ihle. After this, he says, "there was this mad race over about three years to identify new Stat proteins that might be involved in cytokine signaling." So far, Stat1 and 2 have been implicated in signal transduction pathways involving interferon, while researchers have found Stat3, 4, 5, and 6 to be important in the signal transduction pathways of various families of the cytokine interleukin (IL). Stat5-the subject of the 1995 Ihle paper-was first cloned by Bernd Groner at the Frieberg Cancer Center in Germany (H. Wakao et al., EMBO Journal, 13:2182-89, 1994). He was studying how prolactin causes the mammary gland to produce milk. "While this was happening, we were working with Chris Schindler to purify the Stat protein that was induced by erythropoietin [epo] and IL-3, which turned out to be Stat5," says Ihle. His team also showed that the IL-3 family is able to activate multiple forms of Stat5. "Stat5 is also activated by prolactin, epo, other interleukins, as well as many other types of cytokines," explains Ihle. "In fact, one of the reasons why this paper is so highly referenced is because so many people are trying to figure out what Stat5 does in these various systems. Each one of these different receptors is able to recruit and to cause the activation of Stat5. The speculation is that Stat5 plays some role in red-cell proliferation and differentiation, just as it could in prolactin-related lactation in mammary glands." At about the same time that Ihle's group was cloning Stat5, two other groups were working independently to isolate Stat5. One group, headed by Atshushi Miyajima at DNAX Research Institute, a biotech firm in Palo Alto, Calif., cloned the murine Stat5 (A. Miu et al., EMBO J., 14:1166-77, 1995). The other group, headed by Steve McKnight at Tularik Inc., another biotech located in South San Francisco, Calif., cloned Stat5 as an IL-2 induced Stat protein (J. Hou et al., Immunity, 2:321-9, 1995). Ihle calls cytokine signaling a "bloody hot" field. "Everybody is doing experiments to determine the importance of Stat5 activation." More recently, Ihle's group has developed knockout mice in which two highly related Stat5 genes are deleted individually or together. Although he is reluctant to discuss the phenotypes before they are published, he does say that the various phenotypes will be of great interest to those working with Stat5.

Signal Transduction

The Scientist Staff

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