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The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's-like disease

Content Provider	PubMed Central
Author	Enger, Tone Berge Arman, Samad-zadeh Bouchie, Meghan Skarstein, Kathrine Galtung, Hilde Kanli Mera, Toshiyuki Walker, Janice Sue, Menko A. Varelas, Xaralabos Faustman, Denise L. Jensen, Janicke Liaaen Maria, Kukuruzinska
Abstract	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.
Related Links	http://dx.doi.org/10.1038/labinvest.2013.114
Ending Page	1218
Page Count	16
Starting Page	1203
File Format	PDF
ISSN	00236837
e-ISSN	15300307
Journal	Laboratory investigation; a journal of technical methods and pathology
Issue Number	11
Volume Number	93
Language	English
Publisher Date	2013-11-01
Access Restriction	Open
Subject Keyword	Pathology and Forensic Medicine Cell Biology Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Pathology and Forensic Medicine

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