Biology subjects

Luton, F.

Publications and source records attributed to Luton, F..

3 recordsLinked to original sources

bioRxiv2021

OSBP-mediated cholesterol transfer determines epithelial polarity and associated cargo secretion

Golgi lipid environment regulates sorting and cargo secretion. However, the mechanisms that spatiotemporally control the lipid composition of the secretory membranes to drive cargo trafficking are poorly understood. Lipid transfer proteins regulate the concentration of specific lipids at membrane contact sites. We hypothesised that by catalysing cholesterol/PI(4)P exchange at ER-trans-Golgi membrane contact sites the lipid transfer protein oxysterol binding protein (OSBP) affects the secretion of a subset of cargoes. Here, we report that OSBP is a major epithelial protein as its inhibition leads to complete loss of apico-basal polarity. By mapping the OSBP proximity proteome with the biotin ligase TurboID, we found that OSBP controls the secretion of multiple membrane associated proteins, including key polarity determinants such as E-cadherin. Mechanistically, we established that OSBP contributes to E-cadherin secretion by supplying cholesterol to post-Golgi membranes. Importantly, when cells downregulate cell-cell junctions upon epithelial-to-mesenchymal transition, they re-wire their lipid homeostasis and downregulate OSBP as well, thus altering the trafficking of the OSBP-dependent secretory cargoes.

cell biology↗

bioRxiv2021

Arf6 is necessary for high level Wingless signalling during Drosophila wing development

Wnt signalling is a core pathway involved in a wide range of developmental processes throughout the metazoa. In vitro studies have suggested that the small GTP binding protein Arf6 regulates upstream steps of Wnt transduction, by promoting the phosphorylation of the Wnt co-receptor, LRP6, and the release of {beta}-catenin from the adherens junctions. To assess the relevance of these previous findings in vivo, we analyse the consequence of the absence of Arf6 activity on Drosophila wing patterning, a developmental model of Wnt/Wingless signalling. We observed a dominant loss of wing margin bristles and Senseless expression in Arf6 mutant flies, phenotypes characteristic of a defect in high level Wingless signalling. In contrast to previous findings, we show that Arf6 is required downstream of Armadillo/{beta}-catenin stabilisation in Wingless signal transduction. Our data suggest that Arf6 modulates the activity of a downstream nuclear regulator of Pangolin activity in order to control the induction of high level Wingless signalling. Our findings represent a novel regulatory role for Arf6 in Wingless signalling.

developmental biology↗

bioRxiv2020

EFA6B regulates a stop signal for collective invasion in breast cancer

Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes, however additional mutations provide selective advantages to the tumor cells to resist treatment and develop metastases, therefore identification of secondary mutations is of paramount importance. EFA6B (Exchange Factor for ARF6, B) expression is reduced in breast cancer. To study the pro-tumoral impact of the loss of EFA6B we have invalidated its gene in normal human mammary cells. We found that EFA6B knock-out triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal a new EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up new avenues for the treatment of invasive breast cancer.

cancer biology↗