Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.
Noncanonical HIPPO/MST Signaling via BUB3 and FOXO Drives Pulmonary Vascular Cell Growth and Survival.
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DOI：
10.1161/circresaha.121.319100
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发表时间：
2022-03-04
影响因子：
20.1
通讯作者：
Goncharova EA
中科院分区：
文献类型：
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作者：
Kudryashova TV;Dabral S;Nayakanti S;Ray A;Goncharov DA;Avolio T;Shen Y;Rode A;Pena A;Jiang L;Lin D;Baust J;Bachman TN;Graumann J;Ruppert C;Guenther A;Schmoranzer M;Grobs Y;Eve Lemay S;Tremblay E;Breuils-Bonnet S;Boucherat O;Mora AL;DeLisser H;Zhao J;Zhao Y;Bonnet S;Seeger W;Pullamsetti SS;Goncharova EA
哺乳动物Ste 20样激酶（MST）1/2是HIPPO途径的成员，在成人增殖性疾病中充当生长抑制剂。肺动脉高压（PAH）表现为小PA中肺血管细胞增殖和存活增加、肺血管重塑和PA压力升高。MST 1/2在PAH中的作用目前尚不清楚。探讨MST 1和MST 2在肺动脉高压中的作用及机制。使用来自PAH和非病变肺的早期传代肺血管细胞以及具有平滑肌（SM）特异性他莫昔芬诱导的Mst 1/2敲低的小鼠，我们发现，与典型的抗增殖/促凋亡作用相反，MST 1/2在人PAH PA血管平滑肌细胞（PAVSMC）和外膜成纤维细胞（PAAF）中作为促增殖/促存活分子发挥作用并支持SU 5416/缺氧诱导的PH小鼠中建立的肺血管重塑和肺动脉高压（PH）。通过使用无偏蛋白质组学分析、功能获得和丧失方法以及XMU-MP-1对MST 1/2激酶活性的药理学抑制，我们接下来评估了MST 1/2在PAH肺血管细胞中的调节和功能的机制。我们发现，在PAH PAAF中，MST 1/2的促增殖功能是由IL-6依赖的MST 1/2过表达引起的，其诱导PSMC 6依赖的FOXO 3下调和过度增殖。在PAH PAVSMC中，MST 1/2通过与BUB 3形成疾病特异性相互作用发挥作用，并支持细胞外基质和USP 10依赖性BUB 3蓄积、Akt-mTORC 1上调、细胞增殖和存活。支持我们的体外观察，平滑肌特异性Mst 1/2敲低阻止了SU 5416/缺氧诱导的PH小鼠小肌肉PA中Akt-mTORC 1的上调。总之，这项研究描述了MST 1/2在PAH肺血管中的新的促增殖/促存活作用，提供了MST 1/2通过BUB 3和FOXO与PAVSMC和PAAF异常增殖和存活的新机制联系，重塑和PH，并提出了新的治疗干预的靶向途径。
The mammalian Ste20-like kinases (MST) 1/2 are members of the HIPPO pathway that act as growth suppressors in adult proliferative diseases. Pulmonary arterial hypertension (PAH) manifests by increased proliferation and survival of pulmonary vascular cells in small PAs, pulmonary vascular remodeling and the rise of PA pressure. The role of MST1/2 in PAH is currently unknown. To investigate the roles and mechanisms of the action of MST1 and MST2 in PAH. Using early-passage pulmonary vascular cells from PAH and non-diseased lungs and mice with smooth muscle (SM)-specific tamoxifen-inducible Mst1/2 knockdown, we found that, in contrast to canonical anti-proliferative/pro-apoptotic roles, MST1/2 act as pro-proliferative/pro-survival molecules in human PAH PA vascular smooth muscle cells (PAVSMC) and adventitial fibroblasts (PAAF) and support established pulmonary vascular remodeling and pulmonary hypertension (PH) in mice with SU5416/hypoxia-induced PH. By using unbiased proteomic analysis, gain- and loss-of function approaches, and pharmacological inhibition of MST1/2 kinase activity by XMU-MP-1, we next evaluated mechanisms of regulation and function of MST1/2 in PAH pulmonary vascular cells. We found that, in PAH PAAF, the pro-proliferative function of MST1/2 is caused by IL-6-dependent MST1/2 over-expression, which induces PSMC6-dependent down-regulation of FOXO3 and hyper-proliferation. In PAH PAVSMC, MST1/2 acted via forming a disease-specific interaction with BUB3 and supported extracellular matrix- and USP10-dependent BUB3 accumulation, up-regulation of Akt-mTORC1, cell proliferation, and survival. Supporting our in vitro observations, smooth muscle-specific Mst1/2 knockdown halted up-regulation of Akt-mTORC1 in small muscular PAs of mice with SU5416/hypoxia-induced PH. Together, this study describes a novel pro-proliferative/pro-survival role of MST1/2 in PAH pulmonary vasculature, provides a novel mechanistic link from MST1/2 via BUB3 and FOXO to the abnormal proliferation and survival of PAVSMC and PAAF, remodeling and PH, and suggests new target pathways for therapeutic intervention.