VANGL2 (VANGL Planar Cell Polarity Protein 2)

EwS and ECs show a certain degree of molecular similarity, and the original description of EwS as an endothelioma of bone should still be considered as a possibility. We discuss our data in the light of the little work that exists on the innervation and lymphatic supply of bone.

In conclusion, VANGL2 regulates the ATM-p53 pathway-mediated apoptotic response of SCLC to cisplatin by downregulating HINT1, thereby promoting cisplatin resistance. Thus, VANGL2 may serve as a potential therapeutic target for reversing cisplatin resistance in SCLC patients.

This analysis highlighted TNBC's molecular landscape, emphasizing miR-548F-3p's regulatory role. The identified genes, VANGL2, BRCC3, ANP32E, and ANLN, offer insights into TNBC pathogenesis and potential therapeutic targets, laying the foundation for understanding their clinical implications in the intricate landscape of TNBC.

Elevated VANGL2 expression was identified as a predictor of poor prognosis in glioma. Our analysis of the expression and prognostic features of the core PCP gene VANGL2 underscored its critical roles in glioma oncogenesis and progression.

Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1, to an underlying stem-cell state in both early development and in malignancy.

Mechanistically, NF-κB signaling-induced-Vangl2 recruits E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination on p65, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, these findings demonstrate Vangl2 as a suppressor of NF-κB-mediated inflammation and provide insights into the crosstalk between autophagy and inflammatory diseases.

In addition, loss of Vangl2 stearoylation enhances the activation of oncogenic Yes-associated protein 1 (YAP), serine-threonine kinase AKT, and extracellular signal-regulated protein kinase (ERK) signaling and promotes breast cancer cell growth and HRas G12V mutant (HRasV12)-induced oncogenic transformation. Our results reveal a regulation mechanism of Vangl2, and provide mechanistic insight into how fatty acid metabolism and protein fatty acylation regulate PCP signaling and tumorigenesis by core PCP protein lipidation.

Moreover, co-treatment resulted in inactivation of non-canonical Wnt VANGL2-JNK signaling axis. The synergistic impact of inhibition of SQSTM1/P62 and Wnt/β-catenin signaling facilitates the development of a potential therapeutic regimen for TNBC.

Knockdown (KD) of Vangl2 in HC11 cells and primary mammary organoids results in upregulation of Stat5a, Ccnd1 and Csn2, larger acini and organoids, and precocious differentiation; phenotypes are rescued by overexpression of Vangl2, but not Vangl2ΔNLS. Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.

We also found that RNA binding protein fox-1 homolog 3 (RBFOX3) enhances circIGF1R biogenesis by binding to IGF1R pre-mRNA, which in turn suppresses migration and invasion in NSCLC cells. Additionally, the chemotherapeutic drug paclitaxel was shown to impede NSCLC invasion and migration by inducing RBFOX3-mediated circIGF1R biogenesis.RBFOX3 inhibits the invasion and migration of NSCLC cells through the circIGF1R/ miR-1270/VANGL2 axis, circIGF1R has the potential to serve as a biomarker and therapeutic target for NSCLC.

Taken together, these findings support a role for linear (de)ubiquitination in PCP signaling. The association of Met1-Ub chains with PCP complex components offers new opportunities for integrating PCP signaling with OTULIN-dependent immune and inflammatory pathways.

In cultured human gastric epithelial cells, the N terminus of CagA interacted with the C-terminal cytoplasmic tails of VANGL1/2, which impaired Wnt/PCP signaling by inducing the mislocalization of VANGL1/2 from the plasma membrane to the cytoplasm. Thus, CagA may contribute to the development of gastric cancer by subverting a Wnt/PCP-dependent mechanism that restrains pyloric gland stem cell proliferation and promotes enteroendocrine differentiation.