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Aberrant localization of proteins is increasingly being suggested as a causal player in epithelial cancers. Despite this, few studies have investigated how mislocalization of a protein can alter individual biological processes that contribute to cancer progression. Using Ras as a model of transformation, we investigate how localization of the polarity protein Scribble contributes to its tumor-suppressive properties. Wild-type Scribble has been shown to modulate Ras-mitogen-activated protein kinase (MAPK) transformation both in vitro and in vivo. By utilizing a construct that carries a mutation in the LRR domain of Scribble (Scribble P305L) resulting in a cytosolic rather than the usual membrane-bound localization, we report that discrete tumor suppressive properties of Scribble are differentially sensitive to the localization of Scribble. We find that although the Scribble P305L mislocalization mutant can no longer suppress Ras-MAPK-induced invasion or epithelial to mesenchymal transition phenotypes, mislocalized Scribble can still suppress anchorage-independent cell growth. This study illustrates that the manner in which protein mislocalization contributes to cancer is likely complex and highlights the need for careful interrogation as to how cell polarity protein mislocalization, its secondary consequences, and the mutations that give rise to their mislocalization may contribute to specific aspects of cancer progression.

Localization, Not Important in All Tumor-Suppressing Properties: A Lesson Learnt from Scribble