A Novel Interaction between hScrib and PP1[gamma] Downregulates ERK Signaling and Suppresses Oncogene-Induced Cell Transformation

• Published in: PloS one 2013-01, Vol.8 (1), p.e53752
• Main Authors: Seiki, Takayuki, Yano, Tetsu, Subbaiah, Vanitha Krishna, Kozuma, Shiro, Yamashita, Aki, Thomas, Miranda, Taketani, Yuji, Nakagawa, Shunsuke, Banks, Lawrence, Kawana, Kei, Kranjec, Christian, Massimi, Paola, Fujii, Tomoyuki, Nagasaka, Kazunori
• Format: Article
• Language: English
• Subjects: Cellular signal transduction; Disease susceptibility; Genetic aspects; Health aspects; Phosphatases
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0053752

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 1[gamma] (PP1[gamma]) is a major interacting partner of hScrib. This interaction is direct and occurs through a conserved PP1[gamma] 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 PP1[gamma] localization, where loss of hScrib enhances the nuclear translocation of PP1[gamma]. Furthermore, we also show that the ability of hScrib to interact with PP1[gamma] 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 PP1[gamma] and ERK signaling pathways and explains how disruption of hScrib localisation can contribute towards the development of human malignancy.