Biomedical subjects

Xi He

Publications and source records attributed to Xi He.

At least 19 recordsLinked to original sources

PubMed2026

Variance Polygenic Scores (vPGS) as a Tool for Studying Gene-Environment Interactions Associated With Refractive Error.

PURPOSE: Conventional polygenic scores predict an individual's phenotype based on their genetics. By contrast, variance polygenic scores (vPGS) quantify genetic predisposition to phenotypic variance. We tested the hypothesis that a vPGS for refractive error can identify individuals with increased susceptibility to environmental risk factors for myopia. METHODS: Six vPGS construction strategies were evaluated in UK Biobank participants: three variance heterogeneity genome-wide association study (vGWAS) methods and two reweighting schemes. vPGS performance was assessed using two metrics: (i) "Diff"-difference in phenotypic variance in vPGS decile ten versus one; (ii) Spearman correlation of phenotypic variance versus vPGS decile. The optimal vPGS was used to test for vPGS × time spent reading or vPGS × time spent outdoors interactions in children aged 15 years (ALSPAC cohort; n = 3471). RESULTS: Of the vGWAS methods, conditional quantile regression outperformed SCAMPI and Levene's Test. Of the re-weighting schemes, LDpred2 outperformed pruning and thresholding. In an independent sample of UK Biobank participants (n = 19,470), the top-performing vPGS successfully stratified individuals into groups with increasing variance in refractive error, even after adjusting for a conventional PGS (Diff: 2.55, 95% confidence interval [CI], 1.64-3.47; Spearman correlation = 0.87; 95% CI, 0.43-0.93). However, in ALSPAC participants, there was minimal support for vPGS interactions with time reading (P = 0.80) or time outdoors (P = 0.89). CONCLUSIONS: A novel vPGS successfully stratified individuals into groups with relatively high or low genetic susceptibility to refractive error variance. However, the vPGS could not identify individuals at enhanced risk from lifestyle risk factors for myopia.

Humans↗

PubMed2026

Nonuniform Association of Genetic Risk Scores for Intraocular Pressure.

IMPORTANCE: Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma, and genetic risk scores hold promise as a tool for screening for ocular hypertension. However, genetic risk scores for IOP have a nonuniform association across the range of IOP, which reduces their accuracy. OBJECTIVE: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, post hoc genetic association studies were performed using linear and quantile regression in a sample of UK Biobank participants. Data were analyzed from January to September 2025. EXPOSURES: Ninety-eight genetic variants associated with IOP. MAIN OUTCOMES AND MEASURES: Tests were carried out for 98 genetic variants associated with IOP (P < 5.0 ×10-8) to examine (1) dominant or recessive genetic effects, (2) genotype × genotype interactions, (3) genotype × age interactions, and (4) genotype × sex interactions. RESULTS: A total of 98 235 participants (mean [SD] age, 58.1 [7.9] years; 52 168 female [53.1%]) were included in this analysis. More variants exhibited genotype × age interactions than expected by chance (14 of the 98 variants associated with IOP had at least nominal evidence of an interaction with age; P = 3.76 ×10-4). For 12 of these 14 variants, age increased rather than decreased the magnitude of the IOP vs genotype association. However, integrating age interactions into the genetic risk score construction process did not yield improved accuracy (incremental noninteraction model, R2 = 4.05; 95% CI, 3.82-4.31 and interaction model, R2 = 4.04; 95% CI, 3.80-4.27). There was little support for other types of genetic interaction. CONCLUSIONS AND RELEVANCE: In the current work, findings show minimal evidence that nonadditive allelic effects, genotype × genotype interactions, and genotype × sex interactions contributed to the nonuniform association of genetic variants with IOP across quantiles of IOP. Although a genetic risk score for IOP was more accurate in older vs younger individuals, efforts to account for genotype × age interactions in genetic risk score construction did not improve accuracy. These findings suggest other factors, such as gene-environment interactions, contribute to the nonuniform relationship of genetic variants with IOP.

Humans↗

PubMed2007

Association of Dishevelled with the clathrin AP-2 adaptor is required for Frizzled endocytosis and planar cell polarity signaling.

Upon activation by Wnt, the Frizzled receptor is internalized in a process that requires the recruitment of Dishevelled. We describe a novel interaction between Dishevelled2 (Dvl2) and micro2-adaptin, a subunit of the clathrin adaptor AP-2; this interaction is required to engage activated Frizzled4 with the endocytic machinery and for its internalization. The interaction of Dvl2 with AP-2 requires simultaneous association of the DEP domain and a peptide YHEL motif within Dvl2 with the C terminus of micro2. Dvl2 mutants in the YHEL motif fail to associate with micro2 and AP-2, and prevent Frizzled4 internalization. Corresponding Xenopus Dishevelled mutants show compromised ability to interfere with gastrulation mediated by the planar cell polarity (PCP) pathway. Conversely, a Dvl2 mutant in its DEP domain impaired in PCP signaling exhibits defective AP-2 interaction and prevents the internalization of Frizzled4. We suggest that the direct interaction of Dvl2 with AP-2 is important for Frizzled internalization and Frizzled/PCP signaling.

Adaptor Protein Complex 2↗

PubMed2006

LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST.

The low density lipoprotein (LDL) receptor-related protein 5 (LRP5) is a co-receptor for Wnt proteins and a major regulator in bone homeostasis. Human genetic studies have shown that recessive loss-of-function mutations in LRP5 are linked to osteoporosis, while on the contrary, dominant missense LRP5 mutations are associated with high bone mass (HBM) diseases. All LRP5 HBM mutations are clustered in a single region in the LRP5 extracellular domain and presumably result in elevated Wnt signaling in bone forming cells. Here we show that LRP5 HBM mutant proteins exhibit reduced binding to a secreted bone-specific LRP5 antagonist, SOST, and consequently are more refractory to inhibition by SOST. As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Unwinding a path to nuclear beta-catenin.

In this issue of Cell, Yang et al. (2006b) show that PDGF, a growth factor that induces the transition of epithelial cells to mesenchymal cells, stimulates the c-Abl kinase-dependent phosphorylation of p68 RNA helicase. Phosphorylated p68 dissociates beta-catenin from the Axin destruction complex, thereby promoting nuclear beta-catenin signaling independent of Wnt activation.

Animals↗

PubMed2006

Modulation of LRP6-mediated Wnt signaling by molecular chaperone Mesd.

LRP6 is a Wnt coreceptor at the cell surface. Here, we report that a specialized molecular chaperone Mesd modulates LRP6-mediated Wnt signaling and how different LRP6 mutants exhibit differential effects on Wnt signaling. We found that overexpression of increasing amounts of the full-length LRP6 enhances Wnt signaling in a dose dependent manner only in the presence of a co-expression of the molecular chaperone Mesd, which promotes LRP6 folding and maturation to the cell surface. We also demonstrated that LRP6 mutant lacking the intracellular domain impedes LRP6 cell surface expression and Wnt signaling in a dominant-negative fashion by sequestering Mesd from promoting LRP6 folding. Our results present novel mechanisms by which Mesd and LRP6 modulate Wnt signaling.

Cell Line↗

PubMed2006

TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.

Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.

AMP-Activated Protein Kinases↗

PubMed2006

Human ACF1 alters the remodeling strategy of SNF2h.

The human ACF chromatin-remodeling complex (hACF) contains the ATPase motor protein SNF2h and the non-catalytic hACF1 subunit. Here, we have compared the ability of SNF2h and a reconstituted hACF complex containing both SNF2h and hACF1 to remodel a series of nucleosomes containing different lengths of DNA overhang. Both SNF2h and hACF functioned in a manner consistent with sliding a canonical nucleosome. However, the non-catalytic subunit, hACF1, altered the remodeling properties of SNF2h by changing the nature of the requirement for a DNA overhang in the nucleosomal substrate and altering the DNA accessibility profile of the remodeled products. Surprisingly, addition of hACF1 to SNF2h increased the amount of DNA overhang needed to observe measurable amounts of DNA accessibility, but decreased the amount of overhang needed for a measurable binding interaction. We propose that these hACF1 functions might contribute to making the hACF complex more efficient at nucleosome spacing compared with SNF2h. In contrast, the SWI/SNF complex and its ATPase subunit BRG1 generated DNA accessibility profiles that were similar to each other, but different significantly from those of hACF and SNF2h. Thus, we observed divergent remodeling behaviors in these two remodeling families and found that the manner in which hACF1 alters the remodeling behavior of the ATPase is not shared by SWI/SNF subunits.

Adenosine Triphosphatases↗

PubMed2006

Adenomatous polyposis coli (APC) differentially regulates beta-catenin phosphorylation and ubiquitination in colon cancer cells.

Most colorectal cancers have mutations of the adenomatous polyposis coli (APC) gene or the beta-catenin gene that stabilize beta-catenin and activate beta-catenin target genes, leading ultimately to cancer. The molecular mechanisms of APC function in beta-catenin degradation are not completely known. APC binds beta-catenin and is involved in the Axin complex, suggesting that APC regulates beta-catenin phosphorylation. Some evidence also suggests that APC regulates beta-catenin nuclear export. Here, we examine the effects of APC mutations on beta-catenin phosphorylation, ubiquitination, and degradation in the colon cancer cell lines SW480, DLD-1, and HT29, each of which contains a different APC truncation. Although the current models suggest that beta-catenin phosphorylation should be inhibited by APC mutations, we detected significant beta-catenin phosphorylation in these cells. However, beta-catenin ubiquitination and degradation were inhibited in SW480 but not in DLD-1 and HT29 cells. The ubiquitination ofbeta-catenin in SW480 cells can be rescued by exogenous expression of APC. The APC domains required for beta-catenin ubiquitination were analyzed. Our results suggest that APC regulates beta-catenin phosphorylation and ubiquitination by distinct domains and by separate molecular mechanisms.

Adenomatous Polyposis Coli↗

PubMed2006

Threonine 41 in beta-catenin serves as a key phosphorylation relay residue in beta-catenin degradation.

Beta-catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for beta-catenin degradation, and regulation of beta-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. Beta-catenin mutations at Ser45, Thr41, Ser37, and Ser33 perturb beta-catenin degradation and are frequently found in cancers. It is established that Ser45 phosphorylation by casein kinase I (CKI) initiates phosphorylation at Thr41, Ser37, and Ser33 by glycogen synthase kinase 3 (GSK3) and that phosphorylated Ser37 and Ser33 are recognized by the F-box protein beta-TrCP, a component of a ubiquitin ligase complex that mediates beta-catenin degradation. While the roles of Ser45, Ser37, and Ser33 are well documented, the function of Thr41 remains less defined. Here we show that Thr41 strictly acts as a phosphorylation relay residue and that the Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for beta-catenin phosphorylation by GSK3. Beta-catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. These results suggest that Thr41 functions to bridge sequential phosphorylation from Ser45 to Ser37 and provide further insights into the discrete steps and logic in beta-catenin phosphorylation-degradation.

Amino Acid Sequence↗

PubMed2006

Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells.

Adult mesenchymal stem cells (MSCs) derived from bone marrow contribute to the regeneration of multiple types of mesenchymal tissues. Here we describe the functional role of a novel form of cross-talk between the transforming growth factor beta1 (TGF-beta1) and Wnt signaling pathways in regulating the activities of human MSCs. We show that TGF-beta1 induces rapid nuclear translocation of beta-catenin in MSCs in a Smad3-dependent manner. Functionally, this pathway is required for the stimulation of MSC proliferation and the inhibition of MSC osteogenic differentiation by TGF-beta1, likely through the regulation of specific downstream target genes. These results provide evidence for a new mode of cooperation between the TGF-beta and Wnt signaling pathways in this specific cellular context and suggest a potentially important role for this distinct signaling pathway in the control of self-renewal and differentiation of a specific type of MSCs.

Base Sequence↗

PubMed2006

Varp is a Rab21 guanine nucleotide exchange factor and regulates endosome dynamics.

The small GTPases Rab5 and Rab21 are closely related, and play essential roles in endocytic trafficking. Rab5 is regulated by VPS9-domain-containing guanine nucleotide exchange factors. Here, we describe a new VPS9-domain protein with ankyrin repeats, the VPS9-ankyrin-repeat protein (Varp). Varp interacts preferentially with GDP-bound Rab21 and has a much stronger guanine nucleotide exchange activity towards Rab21 than Rab5. Furthermore, RNAi-mediated depletion of endogenous Varp significantly disrupts the activity of Rab21 in HeLa cells. Ectopically expressed Varp mainly localizes to early endosomes and causes enlargement of early endosomes and giant late endosomes. Both the VPS9 domain and ankyrin-repeats are required for the endosomal localization and the activity of Varp in vivo. These results suggest that Varp is a potential Rab21 guanine nucleotide exchange factor and might regulate endosome dynamics in vivo.

Amino Acid Sequence↗

PubMed2006

Exchange bias training effect in coupled all ferromagnetic bilayer structures.

Exchange coupled bilayers of soft and hard ferromagnetic thin films show remarkable analogies to conventional antiferromagnetic/ferromagnetic exchange bias heterostructures. Not only do all these ferromagnetic bilayers exhibit a tunable exchange bias effect, they also show a distinct training behavior upon cycling the soft layer through consecutive hysteresis loops. In contrast with conventional exchange bias systems, such all ferromagnetic bilayer structures allow the observation of training induced changes in the bias-setting hardmagnetic layer by means of simple magnetometry. Our experiments show unambiguously that the exchange bias training effect is driven by deviations from equilibrium in the pinning layer. A comparison of our experimental data with predictions from a theory based upon triggered relaxation phenomena shows excellent agreement.

Journal Article↗

PubMed2006

Activation of Rho and Rac by Wnt/frizzled signaling.

Wnt/Frizzled (Fz) signaling controls developmental, physiological, and pathological processes by means of several distinct pathways. Wnt/Fz activation of the small GTPases Rho and Rac has emerged as a key mechanism that regulates cell polarity and movements during vertebrate gastrulation. In this chapter, we describe biochemical assays for the detection of Wnt/Fz activation of Rho and Rac in both mammalian cells and Xenopus embryo explants.

Animals↗

PubMed2006

Role of the transcription factor Th-POK in CD4:CD8 lineage commitment.

The molecular basis of CD4:CD8 lineage commitment, in particular the mechanism by which the precise correlation between lineage choice and T-cell receptor (TCR) specificity toward class I or II major histocompatibility complex is achieved, remains controversial. Both stochastic/selective and instructive models in various forms have been proposed to explain this correlation. The two main experimental approaches previously employed to elucidate this process have focused on the beginning and end of the process, i.e. the influence of TCR signaling and the alternate transcriptional control of the CD4 and CD8 loci during commitment. The recent finding that the transcription factor Th-POK is necessary and sufficient for CD4 commitment has now provided a direct entry point for studying the intracellular pathways that govern lineage commitment. Here, we review data leading to the identification and characterization of this factor and discuss the implications of these studies in the context of current models of lineage commitment.

Animals↗

PubMed2006

Novel cross talk of Kruppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression.

Epithelial cells of the intestinal mucosa undergo a continual process of proliferation, differentiation, and apoptosis which is regulated by multiple signaling pathways. The Wnt/beta-catenin pathway plays a critical role in this process. Mutations in the Wnt pathway, however, are associated with colorectal cancers. Krüppel-like factor 4 (KLF4) is an epithelial transcriptional factor that is down-regulated in many colorectal cancers. Here, we show that KLF4 interacts with beta-catenin and represses beta-catenin-mediated gene expression. Moreover, KLF4 inhibits the axis formation of Xenopus embryos and inhibits xenograft tumor growth in athymic nude mice. Our findings suggest that the cross talk of KLF4 and beta-catenin plays a critical role in homeostasis of the normal intestine as well as in tumorigenesis of colorectal cancers.

Adenomatous Polyposis Coli Protein↗

PubMed2006

A WNTer wonderland in Snowbird.

The Keystone Symposium on ;Wnt and beta-catenin signaling in development and disease' was held recently in Snowbird, UT, USA. Organized by Mariann Bienz and Hans Clevers, this meeting covered a wide range of topics, including Wnt protein biogenesis, Wnt receptors and signaling pathways, beta-catenin/Tcf complexes and gene expression, Wnt signaling in development, cancer, stem cell biology and regeneration, and therapeutics that target the Wnt/beta-catenin pathway.

Animals↗

PubMed2005

A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.

Signalling by the Wnt family of secreted lipoproteins has essential functions in development and disease. The canonical Wnt/beta-catenin pathway requires a single-span transmembrane receptor, low-density lipoprotein (LDL)-receptor-related protein 6 (LRP6), whose phosphorylation at multiple PPPSP motifs is induced upon stimulation by Wnt and is critical for signal transduction. The kinase responsible for LRP6 phosphorylation has not been identified. Here we provide biochemical and genetic evidence for a 'dual-kinase' mechanism for LRP6 phosphorylation and activation. Glycogen synthase kinase 3 (GSK3), which is known for its inhibitory role in Wnt signalling through the promotion of beta-catenin phosphorylation and degradation, mediates the phosphorylation and activation of LRP6. We show that Wnt induces sequential phosphorylation of LRP6 by GSK3 and casein kinase 1, and this dual phosphorylation promotes the engagement of LRP6 with the scaffolding protein Axin. We show further that a membrane-associated form of GSK3, in contrast with cytosolic GSK3, stimulates Wnt signalling and Xenopus axis duplication. Our results identify two key kinases mediating Wnt co-receptor activation, reveal an unexpected and intricate logic of Wnt/beta-catenin signalling, and illustrate GSK3 as a genuine switch that dictates both on and off states of a pivotal regulatory pathway.

Amino Acid Motifs↗