Biology subjects

Dang, D. K.

Publications and source records attributed to Dang, D. K..

2 recordsLinked to original sources

bioRxiv2018

A Moonlighting Role for SPCA2 in E-cadherin Biogenesis and Suppression of Epithelial-Mesenchymal Transition

Progression of benign tumors to invasive, metastatic cancer requires loss of the cell-adhesion protein E-cadherin. Although intensive efforts have focused on gene repression and silencing mutations, much less is known about posttranslational control of E-cadherin expression in cancer. SPCA2 is a secretory pathway Ca2+-ATPase that is down-regulated in metastatic breast cancer. We show that SPCA2 is tightly co-expressed with epithelial signature genes and required for E-cadherin biogenesis and cell surface expression. Unexpectedly, this function is uncoupled from Ca2+ pumping and mediated by binding to E-cadherin. Loss of SPCA2 is sufficient to disrupt cell-cell adhesion in tumorspheres and elicit mesenchymal gene expression through Hippo-YAP signaling. These findings point to a causal link between low SPCA2 levels and the epithelial-mesenchymal transition required for breast cancer metastasis.\n\nHighlightsO_LISPCA2 is an epithelial marker transcriptionally linked to E-cadherin expression\nC_LIO_LILoss of SPCA2 impairs E-cadherin biogenesis independent of Ca2+ pump activity\nC_LIO_LISPCA2 is required for tumorsphere formation and Hippo-YAP signaling to antagonize epithelial-mesenchymal transition\nC_LIO_LIDown-regulation of SPCA2 in metastatic cancers may contribute to malignancy\nC_LI\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC=\"FIGDIR/small/379586_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@6b1e14org.highwire.dtl.DTLVardef@83edbborg.highwire.dtl.DTLVardef@16cbc5corg.highwire.dtl.DTLVardef@1c2752a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

NHA2 promotes cyst development in an in vitro model of polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. The molecular pathways linking polycystins to cyst development in ADPKD are still unclear. Intracystic fluid secretion via ion transporters and channels plays a crucial role in cyst expansion in ADPKD. Unexpectedly, we observed significant and selective up-regulation of NHA2, a member of the SLC9B family of Na+/H+ exchangers that correlated with cyst size and disease severity in ADPKD patients. Using three-dimensional cultures of MDCK cells to model cystogenesis in vitro, we show that ectopic expression of NHA2 is causal to increased cyst size. Induction of PC1 in MDCK cells inhibited NHA2 expression with concordant inhibition of Ca2+ influx through store-dependent and independent pathways, whereas reciprocal activation of Ca2+ influx by a dominant negative, membrane-anchored C-terminal tail fragment of PC1 elevated NHA2. We show that NHA2 is a target of Ca2+/NFAT signaling and is transcriptionally induced by methylxanthine drugs such as caffeine and theophylline, which are contraindicated in ADPKD patients. Finally, we observe robust induction of NHA2 by vasopressin, which is physiologically consistent with increased levels of circulating vasopressin and up-regulation of vasopressin V2 receptors in ADPKD. Our findings have mechanistic implications on the emerging use of vasopressin V2 receptor antagonists such as tolvaptan as safe and effective therapy for PKD and reveal a potential new regulator of transepithelial salt and water transport in the kidney.

physiology↗