Abstract
SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of deregulations exists: an unexpected SCRIB exon usage pattern appears to mark a more malignant tumor phenotype and significantly correlates with survival. Conserved exons encoding the leucine-rich repeats tend to be overexpressed while others are underused. Mechanistic studies revealed that the underused exons encode part of the protein necessary for interaction with Vimentin and Numa1, a protein which is required for proper positioning of the mitotic spindle. Thus, the inclusion/exclusion of specific SCRIB exons is a mechanistic hallmark of breast cancer, which could potentially be exploited to develop more efficient diagnostics and therapies.
Highlights
In epithelial cells planar polarity is maintained by proteins that are encoded by tumor suppressor genes such as SCRIB (Bilder et al, 2000; Bilder and Perrimon, 2000)
The underused exons encode part of the C-terminal proline-rich domain of Scribble, which we found to become increasingly phosphorylated in mitosis, leading to association with Numa1, a protein known to be crucial for the proper positioning of the mitotic spindle in polarized cells
Scribble S1448 phosphorylation has been reported in several previous studies (Beausoleil et al, 2004, Olsen et al, 2006, Nagasaka et al, 2010) and we have recently reported that S1448 is differentially phosphorylated in response to CD74 overexpression, a phenomenon frequently observed in cancer (Metodieva et al, 2013)
Summary
In epithelial cells planar polarity is maintained by proteins that are encoded by tumor suppressor genes such as SCRIB (Bilder et al, 2000; Bilder and Perrimon, 2000). The protein product of SCRIB, is crucial for the proper maintenance of epithelial cell integrity and function (Zhan et al, 2008); it is required for E-cadherin-mediated cell-cell adhesion and, when its expression is down-regulated, epithelial cells acquire mesenchymal appearance and their migration is augmented (Qin et al, 2005). It was shown recently that Scribble is involved in this process and when its expression is knocked down in Drosophila the orientation of the mitotic spindle becomes random. In this study we show that, in human breast cancer, the expression of several exons, which share very little similarity with the sequence from Drosophila, is decreased relative to the exons encoding the rest of the protein
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