Analysing the impact of nucleo-cytoplasmic shuttling of β-catenin and its antagonists APC, Axin and GSK3 on Wnt/β-catenin signalling

Schmitz, Yvonne; Rateitschak, Katja; Wolkenhauer, Olaf

doi:10.1016/j.cellsig.2013.07.005

Cited by 51 publications

(49 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The sole use of XAV939 in cancer cells inhibited WNT signaling (Huang et al, 2009) by reinforcing the β-catenin destruction complex. However, dual combination of tankyrase inhibition (XAV939) and GSK3β inhibition (CHIR99021) in primed rodent mEpiSCs and primed conventional hESCs paradoxically increased WNT signaling by increasing axin expression, stabilizing the axin-catenin complex, and increasing cytoplasmic retention of β-catenin (Kim et al, 2013;Schmitz et al, 2013). Our hPSC studies herein demonstrated that XAV939 similarly synergizes with CHIR99021 in naïve conditions (i.e.…”

Section: Discussionmentioning

confidence: 76%

Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

et al. 2016

View full text Add to dashboard Cite

The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i). LIF-3i-reverted hPSCs retained normal karyotypes and genomic imprints, and attained defining mouse ESC-like functional features, including high clonal self-renewal, independence from MEK/ERK signaling, dependence on JAK/ STAT3 and BMP4 signaling, and naïve-specific transcriptional and epigenetic configurations. Tankyrase inhibition promoted a stable acquisition of a human preimplantation ICM-like ground state via modulation of WNT signaling, and was most efficacious in efficiently reprogrammed conventional hiPSCs. Importantly, naïve reversion of a broad repertoire of conventional hiPSCs reduced lineage-primed gene expression and significantly improved their multilineage differentiation capacities. Stable naïve hPSCs with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling.

show abstract

Section: Discussionmentioning

confidence: 76%

Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The behavior of four other published models is analyzed and compared with that of the shuttle model (5)(6)(7)(8). Fig.…”

Section: Modelsmentioning

confidence: 99%

“…Despite many molecular advances, the pathway dynamics are still not well understood. Theoretical investigations of the Wnt/β-catenin pathway serve as testbeds for working hypotheses (5)(6)(7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Parameter-free methods distinguish Wnt pathway models and guide design of experiments

MacLean

Rosen

Byrne

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The canonical Wnt signaling pathway, mediated by β-catenin, is crucially involved in development, adult stem cell tissue maintenance, and a host of diseases including cancer. We analyze existing mathematical models of Wnt and compare them to a new Wnt signaling model that targets spatial localization; our aim is to distinguish between the models and distill biological insight from them. Using Bayesian methods we infer parameters for each model from mammalian Wnt signaling data and find that all models can fit this time course. We appeal to algebraic methods (concepts from chemical reaction network theory and matroid theory) to analyze the models without recourse to specific parameter values. These approaches provide insight into aspects of Wnt regulation: the new model, via control of shuttling and degradation parameters, permits multiple stable steady states corresponding to stem-like vs. committed cell states in the differentiation hierarchy. Our analysis also identifies groups of variables that should be measured to fully characterize and discriminate between competing models, and thus serves as a guide for performing minimal experiments for model comparison. T he Wnt signaling pathway plays a key role in essential cellular processes ranging from proliferation and cell specification during development to adult stem cell maintenance and wound repair (1). Dysfunction of Wnt signaling is implicated in many pathological conditions, including degenerative diseases and cancer (2-4). Despite many molecular advances, the pathway dynamics are still not well understood. Theoretical investigations of the Wnt/β-catenin pathway serve as testbeds for working hypotheses (5-12).We focus on models of canonical Wnt pathway processes with the aim of elucidating mechanisms, predicting function, and identifying key pathway components in adult tissues, such as colonic crypts. We compare four preexisting ordinary differential equation models (5-8) and find, using injectivity theory, that for any given conditions and parameter values, none of the models is capable of multiple cellular responses.In many tissues Wnt plays a crucial role in cell fate specification (3). At the base of colonic crypts, cells exist in a stem-like, proliferative phenotype in the presence of Wnt. As these cells' progeny move up the crypt axis they enter a Wnt-low environment and change fate (perhaps reversibly), becoming differentiated, specialized gut cells (13). In neuronal and endocrinal tissues, Wnt/β-catenin data suggest cell fate plasticity under different environmental conditions (14, 15). Here, we introduce a new model motivated by experimental findings not described in previous models (16-18) to investigate bistable switching in the Wnt pathway. We find the new model to be capable of multiple cellular responses; furthermore, our parameter-free techniques identify that molecular shuttling (between cytoplasm and nucleus) and degradation together may serve as a possible mechanism for governing bistability in the pathway, corresponding to, for example, ...

show abstract

“…Wnt signaling stimulates OPG which, in turn, binds and inhibits the receptor activator of nuclear factor kBligand (RANKL) expressed by osteoblasts, thus preventing osteoclast precursor differentiation [18]. Wnt inhibitors allow the catenin degradation complex, consisting of APC, Axin, and GSK3 [19], to degrade cytosolic beta-catenin (Fig. 1b).…”

mentioning

confidence: 97%

From skeletal to cardiovascular disease in 12 steps—the evolution of sclerostin as a major player in CKD-MBD

et al. 2015

View full text Add to dashboard Cite

Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology.

show abstract

Analysing the impact of nucleo-cytoplasmic shuttling of β-catenin and its antagonists APC, Axin and GSK3 on Wnt/β-catenin signalling

Cited by 51 publications

References 66 publications

Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

Tankyrase inhibition promotes a stable human naïve pluripotent state with improved functionality

Parameter-free methods distinguish Wnt pathway models and guide design of experiments

From skeletal to cardiovascular disease in 12 steps—the evolution of sclerostin as a major player in CKD-MBD

Contact Info

Product

Resources

About