Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer

Abstract

Dlg (Discs large), Scrib (Scribble) and Lgl (Lethal giant larvae) are evolutionarily conserved components of a common genetic pathway that link the seemingly disparate functions of cell polarity and cell proliferation in epithelial cells. dlg, scrib and lgl have been identified as tumour suppressor genes in Drosophila, mutations of which cause similar phenotypes, involving disruption of cell polarity and neoplastic overgrowth of tissues. The molecular mechanisms by which Dlg, Scrib and Lgl proteins regulate cell proliferation are not clear, but there is some evidence that epithelial polarisation is required for this regulation. Dlg, Scrib and Lgl are highly conserved between human and Drosophila, and we discuss evidence that these proteins also play a role in cancer progression in humans.

The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge

“…Scribble expression is significantly downregulated in HPVpositive invasive cervical cancers (Massimi et al, 2004;Nakagawa et al, 2004), but it also appears to be lost in a majority of invasive breast cancers and shows altered expression in colon cancer (Gardiol et al, 2006). Thus loss of Scribble is correlated with cancer development, but it is currently not clear whether it represents an important step in the progression of malignant disease (reviewed by Humbert et al (2003)). In Drosophila loss of scribble (scrib) results in the loss of epithelial polarity, a failure to differentiate and overproliferation (Bilder and Perrimon, 2000), suggesting it may serve to directly control tumourigenic growth.…”

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…In Drosophila, mutations in the neoplastic tumor suppressor genes, lgl, dlg and scrib, disrupt polarity of epithelia and simultaneously induce overproliferation of epithelial cells with malignant characteristics, indicating the function of the fly tumor suppressors in coupling cell polarity and cell proliferation (Humbert et al, 2003;Bilder, 2004;Humbert et al, this issue). Consistent with this idea, decreased expression of Lgl, Dlg or Scrib is observed in a variety of human tumors (Cavatorta et al, 2004;Nakagawa et al, 2004;Schimanski et al, 2005;Kuphal et al, 2006).…”

Human papillomavirus type 16 E6 protein interacts with cystic fibrosis transmembrane regulator-associated ligand and promotes E6-associated protein-mediated ubiquitination and proteasomal degradation

“…All of them have multiple PDZ domains, one of which specifically interacts with C-terminal PDZ-binding motif (XTXV/L) of high-risk E6s. They usually play roles in maintaining cell polarity and junctional integrity as well as in scaffolding signal transduction complexes (Sheng and Sala, 2001;Humbert et al, 2003). Therefore, E6-mediated proteasomal degradation of these proteins is considered to cause defective cell-cell adhesion, mislocalization of apicobasolateral signaling receptors and deregulated proliferation of epithelial cells whereby metastatic properties of invasive carcinoma cells might be built up.…”