Defining the Roles of Stat5 Proteins

For this article, Nadia S. Halim interviewed James Ihle, Howard Hughes Medical Institute investigator and chairman of the department of biochemistry, St. Jude Children's Research Hospital, Memphis, Tenn. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. S. Teglund, C. McKay, E. Schuetz, J.M. van Deursen, D. Stravopodis, D. Wang, M. Brown, S. Bodner, G. Grosveld, and J.N. Ihle, "Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses," Cell, 93:841-50, May 29, 1998. (Cited in more than 175 papers since publication) The activation of Stat5 proteins had been studied in an incredibly large number of physiological pathways. However, there was confusion about the importance of these proteins until James Ihle, Howard Hughes Medical Institute investigator and chairman of the department of biochemistry, St. Jude Children's Research Hospital, Memphis, Tenn., and his colleagues used knockout mice to clearly define pathways requiring Stat5 activation. Stat proteins are a direct link from the receptor to the nucleus. Inactive Stat proteins in the cytoplasm are recruited directly to the receptor on cytokine stimulation, which leads to phosphorylation and dimerization. Then the activated Stat dimers travel to the nucleus, where they bind to specific sequences in the promoters of target genes and mediate gene transcription. Because so many molecules activate Stat5 proteins, researchers assumed Stat5 must play a central role in many different physiological pathways. It turns out they were wrong; Stat5 proteins have redundant functions, and sometimes are activated without a purpose. To uncover the functional roles of Stat5a and Stat5b, two genes encoding highly related protein products, Ihle knocked out the genes individually and in combination in mouse models. "Knockout technology gives perhaps the most definitive information about gene function," he explains. This paper demonstrated that Stat5a and Stat5b are required either individually or redundantly, in virtually all the physiological responses associated with growth hormone and prolactin, a hormone that stimulates lactation. Remarkably, Stat5 proteins play either no role, or redundant roles, when responding to structurally related cytokines including erythropoietin (Epo) and thrombopoietin (Tpo). Perhaps the most striking observation was the lack of any effect on Epo functions because numerous studies had implicated Stat5 in red cell proliferation and differentiation. Ihle and his colleagues found that unlike the embryonic lethality that occurs when one eliminates the receptor for Epo or the kinase (Jak2) that is required for the receptor to function, deleting Stat5a/5b resulted in no embryonic lethality or significant changes in embryonic or adult red proliferation or differentiation. James Ihle "We were not very surprised by the results. Based on earlier data, we suspected that Stat5 wasn't as important as everybody thought it was," says Ihle. Though receptors activate multiple pathways, these findings emphasize that only one or a few of those pathways are important in any particular setting. "At the time, this was almost heretical. Why would a cell activate all these pathways if it doesn't need them?" says Ihle. He adds that some people are still baffled by the results with the knockouts and continue to seek to identify situations, such as hematopoietic stress, where the absence of Stat5 proteins might result in some type of phenotype. The following year, the group published a follow-up study that further surprised many researchers in the area. In mice lacking both Stat5a and Stat5b, peripheral T cells exhibited significantly decreased proliferation and failed to undergo cell cycle progression. These phenotypes are not seen in mice lacking Stat5a or Stat5b individually. Indeed, the phenotype was identical in its severity and characteristics to eliminating an essential IL-2 receptor protein chain. Thus, Stat5 proteins, redundantly, are essential mediators of IL-2 signaling in peripheral T cells. 1 "It just shows this incredible specificity in function. Evolution has picked this protein to be a gatekeeper in peripheral T-cell development," explains Ihle. Now that the knockouts have defined the pathways affected by Stat5 activation, the researchers are studying how Stat5 functions in these pathways. "By identifying the targets Stat5 is controlling, we may find out what is so unique about peripheral T cells that it needs Stat5 before proliferation," says Ihle. 1. R. Moriggl et al., "Stat5 is required for IL-2 induced cell cycle progression of peripheral T cells," Immunity, 10:249-59, Feb. 1999.

Defining the Roles of Stat5 Proteins

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Nadia Halim

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October 2000

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