STAT proteins represent an important family of evolutionarily conserved transcription factors that play key roles in diverse biological processes, notably including blood and immune cell development and function. Classically, STAT proteins have been viewed as inducible activators of transcription that mediate cellular responses to extracellular signals, particularly cytokines. In this ‘canonical’ paradigm, latent STAT proteins become tyrosine phosphorylated following receptor activation, typically via downstream JAK proteins, facilitating their dimerization and translocation into the nucleus where they bind to specific sequences in the regulatory region of target genes to activate transcription. However, growing evidence has challenged this paradigm and identified alternate ‘non-canonical’ functions, such as transcriptional repression and roles outside the nucleus, with both phosphorylated and unphosphorylated STATs involved. This review provides a revised framework for understanding the diverse kaleidoscope of STAT protein functional modalities. It further discusses the implications of this framework for our understanding of STAT proteins in normal blood and immune cell biology and diseases such as cancer, and also provides an evolutionary context to place the origins of these alternative functional modalities.

中文翻译：

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STAT 蛋白：免疫和癌症中规范和非规范功能的万花筒

STAT 蛋白代表了一个重要的进化保守转录因子家族，它们在多种生物过程中发挥关键作用，特别是包括血液和免疫细胞的发育和功能。传统上，STAT 蛋白被视为可诱导的转录激活剂，可介导细胞对细胞外信号（尤其是细胞因子）的反应。在这种“规范”范例中，潜伏的 STAT 蛋白在受体激活后变成酪氨酸磷酸化，通常通过下游 JAK 蛋白，促进它们的二聚化和易位到细胞核中，在那里它们与靶基因调控区域中的特定序列结合以激活转录。然而，越来越多的证据对这种范式提出了挑战，并确定了替代的“非规范”功能，例如转录抑制和核外作用，涉及磷酸化和未磷酸化的 STAT。这篇综述为理解 STAT 蛋白功能模式的多样万花筒提供了一个修订的框架。它进一步讨论了这个框架对我们理解正常血液和免疫细胞生物学以及癌症等疾病中的 STAT 蛋白的影响，并提供了一个进化背景来定位这些替代功能模式的起源。