Serine/threonine/tyrosine kinase 1 drives pancreatic carcinogenesis via GSK3β sequestration-mediated Wnt/β-catenin pathway hyperactivation

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Cefan Zhou, Xueying Dong, Shi Li, Yue Xi, Yuan Liu, Xuehong Qian, Ziyan Song, Li Zhou, Rui Zhang, Hao Lyu, Shuai Xiao, Dong Guo, Qi Zhang, Weiyong Liu, Yan Xiong, Zhentian Wang, Chaojun Yan, Zijian Zhang, Haichuan Zhu, Xing-Zhen Chen, Zhiyin Song, Jingfeng Tang
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Abstract

The Wnt/β-catenin pathway is strongly relevant to pancreatic cancer progression, poor prognostic outcomes, and elevated cancer-related mortality. However, the mechanism underlying continuously activated Wnt/β-catenin signaling in pancreatic cancer, a context in which adenomatous polyposis coli (APC) mutations are rarely observed, remains poorly understood. In this study, we investigated the role of STYK1 in regulating canonical Wnt/β-catenin signaling and pancreatic cancer tumorigenesis using the LSL-KrasG12D; Trp53R172H/+; Pdx1Cre mouse model. Our findings demonstrate that STYK1 directly binds to β-catenin and GSK3β, inhibiting GSK3β activity by increasing the level of its kinase-inactive form, which is phosphorylated at S9, and promoting its sequestration into MVBs. We further showed that STYK1-mediated GSK3β sequestration is impaired by autophagy inhibitors or in ATG7 knockout cells, linking this process to autophagic regulation. Structural analysis identified conserved tyrosine-based (Y191QRL194) and dileucine-based (GDLL203-204) sorting motifs in STYK1, which facilitate clathrin/AP2-dependent internalization essential for GSK3β sequestration. The phosphorylation of STYK1 at Y191 by BLK kinase enhances its interaction with AP2, thereby accelerating GSK3β sequestration and subsequent Wnt/β-catenin pathway activation. Notably, inhibitory peptides targeting either the STYK1-β-catenin or the STYK1-GSK3β interface significantly suppressed pancreatic cancer development in vitro and in vivo, underscoring their therapeutic potential. Collectively, these results elucidate a novel STYK1-driven mechanism for Wnt/β-catenin activation in APC-independent pancreatic cancer and provide preclinical evidence for targeting STYK1-mediated signaling as a therapeutic strategy.

Abstract Image

丝氨酸/苏氨酸/酪氨酸激酶1通过GSK3β隔离介导的Wnt/β-catenin通路过度激活驱动胰腺癌发生
Wnt/β-catenin通路与胰腺癌进展、不良预后和癌症相关死亡率升高密切相关。然而,在大肠腺瘤性息肉病(APC)突变很少被观察到的胰腺癌中,Wnt/β-catenin信号持续激活的机制仍然知之甚少。在本研究中,我们利用LSL-KrasG12D研究STYK1在调节典型Wnt/β-catenin信号通路和胰腺癌肿瘤发生中的作用;Trp53R172H / +;Pdx1Cre小鼠模型。我们的研究结果表明,STYK1直接结合β-catenin和GSK3β,通过增加其激酶无活性形式(在S9位点磷酸化)的水平来抑制GSK3β的活性,并促进其被隔离到MVBs中。我们进一步表明,styk1介导的GSK3β隔离被自噬抑制剂或ATG7敲除细胞破坏,将这一过程与自噬调节联系起来。结构分析发现STYK1中基于酪氨酸(Y191QRL194)和二亮氨酸(GDLL203-204)的保守分类基序,促进了GSK3β隔离所必需的网格蛋白/ ap2依赖性内在化。STYK1 Y191位点被BLK激酶磷酸化,增强了其与AP2的相互作用,从而加速了GSK3β的分离和随后的Wnt/β-catenin通路的激活。值得注意的是,针对STYK1-β-catenin或STYK1- gsk3 β界面的抑制肽在体外和体内都能显著抑制胰腺癌的发展,强调了它们的治疗潜力。总之,这些结果阐明了一种新的styk1驱动的apc非依赖性胰腺癌中Wnt/β-catenin激活机制,并为靶向styk1介导的信号传导作为治疗策略提供了临床前证据。
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来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
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