Jaks, STATs, Cytokine Signal Transduction, and Immunoregulation: Are We There Yet?

The discovery of the Jak/STAT pathway goes a long way toward explaining cytokine signaling. The requirement for Jaks in cytokine signaling is very clear, as highlighted by the severe immunodeficiency in humans and mice with Jak3 mutations. Despite their importance for transducing cytokine receptor signals, the Jaks do not seem to contribute to the specificity of cytokine signaling. But STATs do. There are two levels by which specificity of cytokine signaling is achieved: (1) STAT binding to tyrosine- phosphorylated sites on specific cytokine receptors via STAT SH2 domains and (2) STAT binding to specific DNA elements.How do we proceed from here? One important issue is to define more completely the genes that are regulated by cytokines and to analyze their promoters. Compared with our knowledge about genes induced by interferons, much less is known about the genes induced by IL-2, IL-4, and IL-12. Examining the relative contribution of STATs and other transcription factors on the expression of these genes should provide substantial insights into the mechanisms of cytokine action.Presently, our understanding of the STAT function is limited. Although they are translocated to the nucleus after activation, we understand neither the mechanism underlying this translocation nor the reason that are they retained in the cytoplasm prior to stimulation. In addition, two mechanisms have been proposed for attenuating STAT activation: ubiquitination and dephosphorylation (55xRegulation of interferon-gamma-activated STAT1 by the ubiquitin-proteasome pathway. Kim, T.K and Maniatis, T. Science. 1996; 273: 1717–1719Crossref | PubMedSee all References, 38xThe rapid inactivation of nuclear tyrosine phosphorylated Stat1 depends upon a protein tyrosine phosphatase. Haspel, R.L, Salditt-Georgieff, M, and Darnell, J.E.J. EMBO J. 1996; 15: 6262–6268PubMedSee all References). However, the relative importance of these two mechanisms and the identity of the STAT phosphatase are not known. Also, multiple isoforms exist for several STATs, some which function as inhibitors of the full-length forms (Wang et al. 1996xNaturally occurring dominant negative variants of Stat5. Wang, D, Stravopodis, D, Teglund, S, Kitazawa, J, and Ihle, J.N. Mol. Cell. Biol. 1996; 16: 6141–6148Crossref | PubMedSee all ReferencesWang et al. 1996). What is the physiologic function of these alternate STAT species, and how is the process regulated? Last, the solution of the three-dimensional structure of STAT proteins will be of great interest and should improve our understanding of how these transcription factors are regulated, how they bind DNA, and how they accomplish specific binding.Now that a variety of knockout mice have been generated, these mice will provide excellent vehicles for reconstitution studies with mutated version of Jaks and STATs to elucidate structure–function relationships as they relate to the organism. Moreover, given the specific phenotypes of STAT1, STAT4, and STAT6 knockout mice, the search for human mutations of these genes seems warranted. For STAT3, which has global effects on development, it will be important to investigate the loss of such a factor in a tissue- and organ-specific manner to delineate its role in the adult animal.A particularly important issue is how cytokines regulate cell growth and the contribution of Jaks and STATs to this process. Clearly, other pathways, including the Ras/Raf/MAPK and phosphatidylinositol 3-kinase/AKT pathways are also turned on by cytokine receptors. How do Jaks and STATs interact with this pathway? Recent data show that STATs also serve as adapter molecules for the coupling of cytokine receptors with phosphatidylinositol 3-kinase (Pfeffer et al. 1997xSTAT3 as an adapter to couple phosphatidylinositol 3-kinase to the IFNAR1 chain of the type I interferon receptor. Pfeffer, L.M, Mullersman, J.E, Pfeffer, S.R, Murti, A, Shi, W, and Yang, C.H. Science. 1997; 276: 1418–1420Crossref | PubMed | Scopus (206)See all ReferencesPfeffer et al. 1997). Understanding the intersections and crosstalk in these signal pathways is essential. Conversely, it is also pertinent that STATs may have direct effects on inhibiting proliferation by induction of cyclin-dependent kinase inhibitors, such as p21 WAF1/CIP1 (Chin et al. 1996xCell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Chin, Y.E, Kitagawa, M, Su, W.C, You, Z.H, Iwamoto, Y, and Fu, X.Y. Science. 1996; 272: 719–722Crossref | PubMedSee all ReferencesChin et al. 1996). This may explain the antiproliferative effects of the interferons.Finally, utilizing model organisms like C. elegans, Drosophila, Dictyostelium, and zebrafish to analyze the components involved in growth and development will undoubtedly promote advances in understanding mammalian cellular differentiation.So, an appropriate response to the cries from the back seat is “We are not there yet, but keep your eyes open or you'll miss something exciting.”