Thomas Daniel, Guthridge Mark, Woodcock Jo, Lopez Angel
Cytokine Receptor Laboratory, Division of Human Immunology Hanson Institute, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia.
Curr Top Dev Biol. 2005;67:285-303. doi: 10.1016/S0070-2153(05)67009-3.
Tyrosine and serine phosphorylation are central to cellular signaling in growth and development. 14-3-3 proteins function as dimeric phosphoserine-binding proteins with documented interactions throughout the eukaryotic proteome and are highly conserved in both the animal and plant kingdoms. Binding of 14-3-3 to a client protein can have a range of context-dependent effects, including conformational change, enzyme inhibition, a shielding effect, re-localization, and bridging between two molecules. Proteome-based strategies utilizing mass spectrometry have revealed an unprecedented central stage for 14-3-3 in signal transduction with interacting partners composing at least 0.6% of the cellular proteome. 14-3-3 has been shown to bind to the human GM-CSF, IL-3, and IL-5 receptors and is required for the transmission of cell survival. 14-3-3 is involved in survival-specific signals, acting not only at the receptor level but also at critical steps downstream of the receptor. This phosphoserine-mediated pathway works independently of tyrosine kinases, highlighting an alternative mechanism of signaling for this receptor family. Other growth factor receptors and their adaptors are also being shown to associate with 14-3-3 and/or have putative 14-3-3 interaction sequences, such as the prolactin receptor, IGF-1 receptor, and some G-protein coupled receptors. 14-3-3 proteins are remarkably conserved through eukaryotic organisms and in Drosophila are required for photoreceptor development, learning, timing of cell cycles, and maintenance of cellular polarity. These findings are elevating our initial description of biochemical interactions to a better understanding of 14-3-3 function at the level of the whole organism. Further study should explore the integration of phosphoserine and phosphotyrosine signaling by 14-3-3 proteins and the role of isoform-specific functions in higher organisms. The prevalence of functional 14-3-3 binding sites throughout the proteome, and especially among growth factor receptors and signaling molecules, reflects a global role for 14-3-3 in multiple cellular decision making.
酪氨酸和丝氨酸磷酸化在生长和发育过程中的细胞信号传导中起着核心作用。14-3-3蛋白作为二聚体磷酸丝氨酸结合蛋白发挥作用，在整个真核生物蛋白质组中都有记录的相互作用，并且在动物和植物界中都高度保守。14-3-3与客户蛋白的结合可以产生一系列依赖于上下文的效应，包括构象变化、酶抑制、屏蔽效应、重新定位以及两个分子之间的桥接。利用质谱的基于蛋白质组的策略揭示了14-3-3在信号转导中前所未有的核心地位，其相互作用伙伴至少占细胞蛋白质组的0.6%。已证明14-3-3与人GM-CSF、IL-3和IL-5受体结合，并且是细胞存活信号传递所必需的。14-3-3参与存活特异性信号传导，不仅在受体水平起作用，还在受体下游的关键步骤起作用。这种磷酸丝氨酸介导的途径独立于酪氨酸激酶起作用，突出了该受体家族的另一种信号传导机制。其他生长因子受体及其衔接蛋白也被证明与14-3-3相关联和/或具有推定的14-3-3相互作用序列，例如催乳素受体、IGF-1受体和一些G蛋白偶联受体。14-3-3蛋白在真核生物中非常保守，在果蝇中，它是光感受器发育、学习、细胞周期定时和细胞极性维持所必需的。这些发现正在将我们对生化相互作用的初步描述提升到对14-3-3在整个生物体水平上功能的更好理解。进一步的研究应该探索14-3-3蛋白对磷酸丝氨酸和磷酸酪氨酸信号传导的整合作用以及异构体特异性功能在高等生物中的作用。功能性14-3-3结合位点在整个蛋白质组中普遍存在，尤其是在生长因子受体和信号分子中，这反映了14-3-3在多个细胞决策中的全局作用。
