Abstract
Previous studies have shown that the cell polarity regulator hScrib interacts with, and consequently controls, the ERK signaling pathway. This interaction occurs through two well-conserved Kinase Interacting Motifs, which allow hScrib to bind ERK1 directly, resulting in a reduction in the levels of phospho-ERK. This suggests that hScrib might recruit a phosphatase to regulate this signaling pathway. Using a proteomic approach we now show that Protein Phosphatase 1γ (PP1γ) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1γ interaction motif on the hScrib protein, and this interaction appears to be required for hScrib's ability to downregulate ERK phosphorylation. In addition, hScrib also controls the pattern of PP1γ localization, where loss of hScrib enhances the nuclear translocation of PP1γ. Furthermore, we also show that the ability of hScrib to interact with PP1γ is important for the ability of hScrib to suppress oncogene-induced transformation of primary rodent cells. Taken together, these results demonstrate that hScrib acts as a scaffold to integrate the control of the PP1γ and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy.
Highlights
The control of cell polarity and the maintenance of tissue architecture are intimately related and are, in part, controlled by a tri-partite macromolecular signaling complex consisting of the Scrib complex, the Par complex and the Crumbs complex [1,2]
Phosphatase 1c (PP1c) is a direct binding partner of hScrib Based on our previous studies we reasoned that down-regulation of ERK phosphorylation by hScrib might involve the recruitment of a protein phosphatase [19]
Co-immunoprecipitated hScrib was detected by western blotting, and the results in Figure 1C show a significant degree of co-immunoprecipitation of hScrib with PP1c in both cell lines
Summary
The control of cell polarity and the maintenance of tissue architecture are intimately related and are, in part, controlled by a tri-partite macromolecular signaling complex consisting of the Scrib complex, the Par complex and the Crumbs complex [1,2]. It is clear that the loss of control of these pathways is a common event during the development of diverse human malignancies [1,4,5,6,7]. These defects are evident at the later stages of malignant progression, and a variety of studies in both Drosophila and transgenic mice have provided additional supporting evidence of tumour suppressor activity for the various components of these signaling complexes [8,9,10,11]. Since hScrib has no known phosphatase activity itself, it seemed possible that a protein phosphatase might be recruited by hScrib to fully inactivate the ERK signaling pathway
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