Scrib is required for epithelial cell identity and prevents epithelial to mesenchymal transition in the mouse

Abstract

The integrity and function of epithelial tissues depends on the establishment and maintenance of defining characteristics of epithelial cells, cell-cell adhesion and cell polarity. Disruption of these characteristics can lead to the loss of epithelial identity through a process called epithelial to mesenchymal transition (EMT), which can contribute to pathological conditions such as tissue fibrosis and invasive cancer. In invertebrates, the epithelial polarity gene scrib plays a critical role in establishing and maintaining cell adhesion and polarity. In this study we asked if the mouse homolog, Scrib, is required for establishment and/or maintenance of epithelial identity in vivo. To do so, we conditionally deleted Scrib in the head ectoderm tissue that gives rise to both the ocular lens and the corneal epithelium. Deletion of Scrib in the lens resulted in a change in epithelial cell shape from cuboidal to flattened and elongated. Early in the process, the cell adhesion protein, E-cadherin, and apical polarity protein, ZO-1, were downregulated and the myofibroblast protein, αSMA, was upregulated, suggesting EMT was occurring in the Scrib deficient lenses. Correlating temporally with the upregulation of αSMA, Smad3 and Smad4, TGFβ signaling intermediates, accumulated in the nucleus and Snail, a TGFβ target and transcriptional repressor of the gene encoding E-cadherin, was upregulated. Pax6, a lens epithelial transcription factor required to maintain lens epithelial cell identity also was downregulated. Loss of Scrib in the corneal epithelium also led to molecular changes consistent with EMT, suggesting that the effect of Scrib deficiency was not unique to the lens. Together, these data indicate that mammalian Scrib is required to maintain epithelial identity and that loss of Scrib can culminate in EMT, mediated, at least in part, through TGFβ signaling.

Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer

“…In addition, Scribble is required for directional migration, promotes epithelial identity and suppresses epithelial to mesenchymal transition in mammary and corneal epithelial cells (4, 5, 39). Together, these observations suggest a working model that SCRIB normally promotes epithelial differentiation and loss of expression results in mesenchymal transition and tumorigenesis.…”

“…Conversely, overexpression of SCRIB in mammary epithelial cells promotes epithelial differentiation by suppressing expression of epithelial mesenchymal transition regulators in a Ras/MAPK dependent manner (4). Conditional deletion of SCRIB in the corneal epithelium decreases E-cadherin expression and promotes mesenchymal transition suggesting that SCRIB is required for maintaining epithelial cell identity (5). In addition, SCRIB also regulates the Hippo signaling pathway (6), and signal transducer and activator of transcription (STAT) (7).…”

Scribble is required for pregnancy-induced alveologenesis in the adult mammary gland

“…Conditional loss studies have identified SCRIB as a regulator of biology in both lung and corneal epithelial cells (Yates et al, 2013;Yamben et al, 2013). In the mammary gland, loss of SCRIB activates RAS-MAPK signaling, and induces multilayering of the luminal epithelium and hyperbranching of ductal structures (Godde et al, 2014).…”

Studying Interrelation of PDLIM4 with the Model of CD74-Mediated Development of Breast Cancer

“…Based on the previous research data it is possible to assume that described proteins are components of the same signaling cascades involved in BC developments. It is known, in particular, that CD74, acting as a cellular receptor for MIF-factor that inhibits migration of macrophages can activate ERK signaling path (Ras-ERK, MAPK/ERK), one of the key and most well studied signaling paths of MAPK (mutagen-activated protein kinase) (Fan et al, 2011;Yamben et al, 2013). The previous results of studying the role of PDLIM4 in BC development also showed its interrelation with separate components of a MAPK signaling path (Kravchenko et al, 2016).…”