The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's syndrome.
The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's syndrome.
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DOI：
10.1038/labinvest.2013.114
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发表时间：
2013-11
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中科院分区：
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干燥综合征(SS)是一种复杂的自身免疫性疾病，主要累及唾液和泪腺，发病率高。虽然流行的教条是免疫系统病理驱动SS，但越来越多的证据表明结构性缺陷，包括E-钙粘附素黏附缺陷，与其病因有关。我们已经证明E-钙粘附素在小鼠唾液腺的发育中起着关键作用，它通过组织腺泡和导管前体细胞的顶底极性，并通过信号传递分化的导管细胞存活。最近，E-钙粘素连接被证明与河马信号通路的效应器相互作用，河马信号通路是调节器官大小、细胞增殖和分化的核心通路。我们现在表明，河马信号是SMG分支形态发生所必需的，并参与了SS的病理生理学。在SMG发育过程中，河马信号通路效应器TAZ的磷酸化程度越来越高，并与E-钙粘蛋白和α-连环蛋白联系在一起，这与河马信号的激活一致。抑制Lats2，一种促进TAZ磷酸化的上游激酶，会导致SMG的畸形生成和受损的导管形成。来自NOD小鼠的SMG是SS的小鼠模型，其表型复制了Lats2抑制的SMG，并显示出包括TAZ在内的E-钙粘素连接成分的减少。重要的是，来自人类SS患者的嘴唇标本显示TAZ从连接区到细胞核的错误定位，与细胞外基质成分、纤维连接蛋白和CTGF的积累一致，这是TAZ的已知下游靶点。我们的研究表明，河马信号在SMG分支形态发生中起着至关重要的作用，并提供了证据表明该途径的缺陷与人类的SS有关。
Sjogren's syndrome (SS) is a complex autoimmune disease that primarily affects salivary and lacrimal glands and is associated with high morbidity. Although the prevailing dogma is that immune system pathology drives SS, increasing evidence points to structural defects, including defective E-cadherin adhesion, to be involved in its etiology. We have shown that E-cadherin plays pivotal roles in the development of the mouse salivary submandibular gland (SMG) by organizing apical-basal polarity in acinar and ductal progenitors and by signaling survival for differentiating duct cells. Recently, E-cadherin junctions have been shown to interact with effectors of the Hippo signaling pathway, a core pathway regulating organ size, cell proliferation and differentiation. We now show that Hippo signaling is required for SMG branching morphogenesis and is involved in the pathophysiology of SS. During SMG development, a Hippo pathway effector, TAZ, becomes increasingly phosphorylated and associated with E-cadherin and α-catenin, consistent with the activation of Hippo signaling. Inhibition of Lats2, an upstream kinase that promotes TAZ phosphorylation, results in dysmorphogenesis of the SMG and impaired duct formation. SMGs from NOD mice, a mouse model for SS, phenocopy the Lats2-inhibited SMGs and exhibit a reduction in E-cadherin junctional components, including TAZ. Importantly, labial specimens from human SS patients display mislocalization of TAZ from junctional regions to the nucleus, coincident with accumulation of extracellular matrix components, fibronectin and CTGF, known downstream targets of TAZ. Our studies show that Hippo signaling plays a crucial role in SMG branching morphogenesis and provide evidence that defects in this pathway are associated with SS in humans.
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影响因子：
30.8
作者：
Entesarian, M;Matsson, H;Dahl, N
通讯作者：
Dahl, N
影响因子：
4.6
作者：
Hoffman, MP;Kidder, BL;Larsen, M
通讯作者：
Larsen, M
影响因子：
--
作者：
Ewert, Patricia;Aguilera, Sergio;Gonzalez, Maria-Julieta
通讯作者：
Gonzalez, Maria-Julieta
TAZ 促进细胞增殖和上皮间质转化，并受 hippo 通路抑制
影响因子：
5.3
作者：
Lei, Qun-Ying;Zhang, Heng;Guan, Kun-Liang
通讯作者：
Guan, Kun-Liang
影响因子：
56.9
作者：
Kodama, S;Kühtreiber, W;Faustman, DL
通讯作者：
Faustman, DL