The mechanisms and implications of hScrib regulation of ERK

Abstract

Scribble is a potential tumour suppressor protein, whose loss is a frequent event in late stage cancer development. In both Drosophila and mammalian model systems, Scribble has been shown capable of regulating cell polarity, cell proliferation and apoptosis. Although several interacting partners, including βPiX, have been identified that help to explain how Scribble can regulate cell polarity and migration, little is known about how Scribble can control cell proliferation. Recent work from our laboratory has shown that Scribble can directly regulate the ERK signaling pathway. This is mediated by a direct protein-protein interaction between Scribble and ERK, which has two components. In the first, Scribble appears to anchor ERK at membrane-bound sites, with the loss of Scribble enhancing ERK nuclear translocation. In the second, Scribble can decrease the levels of active phosphorylated ERK, a function that is dependent upon the ability of Scribble to bind ERK directly. One of the consequences of this activity of Scribble is the inhibition of EJ-ras induced cell transformation. These results provide some of the first direct mechanistic information on how Scribble can regulate cell proliferation and, furthermore, they provide indications as to the identity of other signaling intermediates that may be recruited by Scribble to directly regulate mitogenic signaling pathways.

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Acknowledgements

Work in the LB laboratory is supported by research grants from the Associazione Italiana per la Ricerca sul Cancro, Association for International Cancer Research and Telethon. K.N. was supported by the Yoshida (YKK) Scholarships Foundation. We are grateful to Miranda Thomas for comments on the manuscript.

Figures and Tables

Figure 1 Schematic diagram showing the human Scribble protein. The major functional domains on Scribble are shown including the Leucine Rich Repeats (LRRS) and the 4 PDZ domains. Also shown are the N and C terminal KIM sites and their corresponding phospho-acceptor sites (S853 and S1448), together with the location of the PKA phospho-acceptor site (S1445).

Figure 2 Scribble integrates signaling pathways to control polarized cell migration, cell proliferation and cell invasion. Scribble interacts directly with ERK and βPix. It controls directional migration through regulating the activity of Cdc42 via βPix and also controls the ERK signaling cascade through controlling ERK activity and localisation. This activity of Scribble has implications for controlling cell proliferation and invasion, and we propose that Scribble regulation of ERK is achieved by the direct recruitment of a phosphatase by Scribble. The consequences of ERK phosphorylation of Scribble at S853 and S1448 are currently unknown.

Table 1 Sequence alignments of the scribble protein from different species

Table 2 Known interacting partners of scribble and their sites of interaction on the scribble protein

Extra View to: Nagasaka K, Pim D, Massimi P, Thomas M, Tomaic V, Subbaiah VK, et al. The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction. Oncogene 2010; 29:5311 - 5321; PMID: 20622900; http://dx.doi.org/10.1038/onc.2010.265

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