TYK2-dependent STAT1 and STAT3 phosphorylation

STAT1 and STAT3 are phosphorylated in ALK+ and ALK- ALCL in a manner that depends on active TYK2. Knockout or inhibition of TYK2 in ALCL human and mouse models abrogates STAT1 and STAT3 phosphorylation, decreases expression of MCL1 and increases cell death, implicating a TYK2-STAT-MCL signaling cascade in ALCL cell survival (Prutsch et al, 2019). Direct phosphorylation of STAT1 and STAT3 by TYK2 has not been demonstrated, nor has direct binding of either STAT to the promoter of the MCL1 gene, despite previous evidence supporting a JAK/STAT/MCL1 pathway (Prutsch et al, 2019; Rassidakis et al, 2002). Moreover, although autocrine stimulation of IL10 and IL22 has been implicated in the activation of TYK2 in these cells, the precise mechanism for TYK2 upregulation in ALCLs has not been determined (Prutsch et al, 2019).<br>STAT3 is a known effector of NPM1-ALK-mediated signaling, but the role of STAT1 is somewhat less clear (Crescenzo et al, 2015; Chiarle et al, 2005; reviewed in Chiarle, 2008). STAT1 has been described as a tumor suppressor in ALCL, and one study showed that STAT1 is downregulated in ALCL in an NPM1-ALK- and proteasome-dependent fashion (Wu et al, 2015; Avalle et al, 2012; Zhang and Liu, 2017).

STAT1和STAT3在ALK+和ALK-的ALCL中，其磷酸化方式依赖于活性TYK2。在ALCL的人源和鼠源模型中，敲除或抑制TYK2将导致STAT1和STAT3的磷酸化消失，降低MCL1的表达并增加细胞死亡，从而表明TYK2-STAT-MCL信号通路在ALCL细胞的存活中发挥重要作用（Prutsch等，2019年）。尽管已有证据支持JAK/STAT/MCL1通路（Prutsch等，2019年；Rassidakis等，2002年），但尚未证实TYK2直接磷酸化STAT1和STAT3，也未观察到STAT与MCL1基因启动子的直接结合。此外，尽管有研究表明这些细胞中IL10和IL22的自分泌刺激可能参与TYK2的激活，但ALCLs中TYK2上调的确切机制尚未明确（Prutsch等，2019年）。STAT3是NPM1-ALK介导的信号传导已知效应器，但STAT1的作用尚不明确（Crescenzo等，2015年；Chiarle等，2005年；参见Chiarle，2008年的综述）。STAT1在ALCL中被描述为一种肿瘤抑制因子，一项研究表明，STAT1在ALCL中通过NPM1-ALK和蛋白酶体依赖性方式下调（Wu等，2015年；Avalle等，2012年；张和刘，2017年）。