Thorax Online First, published on April 17, 2017 as 10.1136/thoraxjnl-2016-209753 State of the art review ‘WNT-er is coming’: WNT signalling in chronic lung Thorax: first published as 10.1136/thoraxjnl-2016-209753 on 17 April 2017. Downloaded from diseases H A Baarsma,1 M Königshoff1,2 1Comprehensive Pneumology ABSTRACT involved in the phosphorylation and subsequent Center, Helmholtz Center Chronic lung diseases represent a major public health degradation of β-catenin. Binding of a specific WNT Munich, Ludwig Maximilians University Munich, University problem with only limited therapeutic options. An ligand (eg, WNT-3A) to one of the Frizzled recep- Hospital Grosshadern, Member important unmet need is to identify compounds and tors (FZD1 through FZD10) and subsequent activa- of the German Center for Lung drugs that target key molecular pathways involved in the tion of the low-density lipoprotein receptor-related Research (DZL), Munich, pathogenesis of chronic lung diseases. Over the last proteins 5 and 6 (LRP5/6) co-receptors triggers an Germany 2 decade, there has been extensive interest in investigating intracellular signalling cascade, which results in Division of Pulmonary ‘β ’ Sciences and Critical Care Wingless/integrase-1 (WNT) signalling pathways; and inactivation of the -catenin destruction complex . Medicine, Department of WNT signal alterations have been linked to pulmonary Hence, cytosolic β-catenin can accumulate, translo- Medicine, University of disease pathogenesis and progression. Here, we cate to the nucleus and, in association with T cell Colorado School of Medicine, comprehensively review the cumulative evidence for WNT factor/lymphoid enhancer factor-1 (TCF/LEF) Aurora, Colorado, USA pathway alterations in chronic lung pathologies, including family of transcription factors, induce specific gene 1 Correspondence to idiopathic pulmonary fibrosis, pulmonary arterial expression (figure 1). Professor M Königshoff, hypertension, asthma and COPD. While many studies Activation of non-canonical WNT signalling also Division of Pulmonary Sciences have focused on the canonical WNT/β-catenin signalling relies on the binding of specific WNT ligands (eg, and Critical Care Medicine, pathway, recent reports highlight that non-canonical WNT WNT-4 or WNT-5A) to FZD receptors; however, Department of Medicine, fi University of Colorado School signalling may also signi cantly contribute to chronic lung it appears to be independent of LPR5/6 co- of Medicine, Anschutz Medical pathologies; these studies will be particularly featured in receptors. Non-canonical WNT signalling results in Campus M/S C 272, 12700 E this review. We further discuss recent advances uncovering the activation of intracellular signalling molecules 19th Avenue, RC2, 9th Floor, the role of WNT signalling early in life, the potential of involved in planar cell polarity (PCP pathway), Aurora, CO 80045-2581, USA; pharmaceutically modulating WNT signalling pathways calcium/calmodulin-dependent protein kinase II Melanie.Koenigshoff@ 2+ ucdenver.edu and highlight (pre)clinical studies describing promising (Ca /CAMKII) signalling and/or various less well new therapies for chronic lung diseases. defined downstream effector molecules (figure 2). Received 20 November 2016 Notably, some classically defined non-canonical Revised 1 March 2017 WNT ligands are able to negatively influence Accepted 16 March 2017 THE BASICS: WNT SIGNALLING canonical WNT/β-catenin signalling. Moreover, The Wingless/integrase-1 (WNT) signalling path- single WNT ligands can activate multiple signalling http://thorax.bmj.com/ ways represent classical developmentally active path- pathways suggesting that WNT ligands are not ways required for proper organ development. WNT intrinsically canonical or non-canonical. Selectivity ligands comprise a family of secreted glycoproteins in receptor-ligand binding (eg, FZD-WNT inter- that instruct cells in the respiratory system to adopt action) likely dictates the outcome of downstream particular fates throughout lung development as signalling.23Indeed, a biochemical study demon- well as tissue homoeostasis in adulthood. In strated that WNT ligands can selectively bind to humans, the WNT ligand family is composed of 19 specific FZD receptors, and that respective distinct ligands, which are historically classified WNT-FZD pairs exert functional selectivity in on September 30, 2021 by guest. Protected copyright. based on their amino acid sequence rather than their downstream signalling.4 These data emphasise the functional properties. Classically, WNT signalling interconnectivity and complexity of canonical and – has been separated into canonical and non-canonical non-canonical WNT signalling157 (figure 2). The signalling. WNT signalling that relies on the activa- dynamics of WNT and FZD expression in complex tion of the transcriptional coactivator β-catenin is biological systems in vivo is currently unknown, designated as canonical WNT signalling (figure 1) thus a better understanding of receptor-ligand and pathways activated by WNT ligands independ- interactions in WNT signalling is required to ently of β-catenin are classified as non-canonical decipher how exactly WNT ligands function. As WNT pathways (figure 2). We start off with an such, the separation of WNT signalling in purely explanation of the well described canonical WNT canonical and non-canonical signalling pathways signalling pathway, in which WNT ligands activate appears to be outdated and certainly oversimplifies β-catenin-mediated gene transcription. In the the complexity of this signalling pathway; however absence of specific WNT ligands, cytosolic β-catenin for uniformity reasons we maintain this nomencla- is tightly regulated by the so-called ‘β-catenin ture in this review. Whenever possible, we mention destruction complex’, a multiprotein complex that which WNT ligands, receptors and/or downstream targets β-catenin via phosphorylation and ubiquiti- signalling molecules are involved when we refer to To cite: Baarsma HA, nation for proteasomal degradation (figure 1). The canonical or non-canonical WNT signalling. Königshoff M. Thorax ‘β ’ Published Online First: core of the -catenin destruction complex is com- Over the last decade, there has been extensive [please include Day Month posed of the proteins axin, adenomatous polyposis interest in investigating WNT signalling pathways in Year] doi:10.1136/thoraxjnl- coli, casein kinase-1 and glycogen synthase chronic lung diseases. Several components of the 2016-209753 kinase-3β (GSK-3β). The latter is the primary kinase WNT pathways serve as potent oncogenes and Baarsma HA, Königshoff M. Thorax 2017;0:1–14. doi:10.1136/thoraxjnl-2016-209753 1 Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BTS) under licence. State of the art review Thorax: first published as 10.1136/thoraxjnl-2016-209753 on 17 April 2017. Downloaded from Figure 1 Schematic representation of canonical WNT/β-catenin signalling. Left side: cytosolic β-catenin is rapidly degraded by the β-catenin destruction complex in the absence of extracellular WNT ligands. The core of the β-catenin destruction complex is composed of: adenomatous polyposis coli (APC), axin, casein kinase-1 (CK-1) and glycogen synthase kinase-3 (GSK-3). GSK-3 is the primary kinase involved in the degradation of β-catenin. Right side: an extracellular WNT ligand binds and activates Frizzled (FZD) and the low density lipoprotein receptor-related proteins 5 and 6 (LRP5/6), which results in the activation of and intercellular signalling cascade that leads to the inhibition of the β-catenin destruction complex. Hence, β-catenin can accumulate and translocate to the nucleus to induce gene transcription. In the nucleus β-catenin can associate with various transcriptional coactivators, including T cell factor (TCF) and lymphoid enhancer factor (LEF). http://thorax.bmj.com/ WNT signalling has been linked to lung cancer, which has been canonical or non-canonical signalling, can result in severe lung extensively reviewed previously and will not be included in this phenotypes, which partially resemble lung diseases observed – – review.5813 Here, we aimed to comprehensively review cumu- during adulthood.52023 Moreover, deletion of β-catenin in epi- lative evidence for WNT pathway alterations in chronic lung thelial cells of embryonic lungs results in disrupted lung mor- pathologies, including idiopathic pulmonary fibrosis (IPF), pul- phogenesis.24 In contrast, overexpression of a truncated, monary arterial hypertension (PAH), asthma and COPD. Early constitutively active form of β-catenin in Clara cell secretory on September 30, 2021 by guest. Protected copyright. studies have largely focused on the canonical WNT/β-catenin protein (CCSP) positive cells (Club cells) does not influence signalling pathway and only recently several reports suggest that lung morphogenesis before birth, but leads postnatally to goblet non-canonical WNT signalling might also contribute signifi- cell hyperplasia, pulmonary tumour development and airspace cantly to chronic lung pathologies. These studies will be high- enlargement.25 Collectively, these studies highlight the import- lighted in this review. We further discuss recent advances in our ance of strict spatiotemporal control of WNT signalling for knowledge on the role of WNT signalling in early life, and proper lung development and lung physiology early in life and feature novel developments and the potential application of thereafter into adulthood. More recently,