Dimerization and Cytoplasmic Localization Regulate Hippo Kinase Signaling Activity in Organ Size Control

Abstract

Background: Hippo plays critical roles in organ size control, and the regulation of its activity remains poorly characterized. Results: N-terminal dimerization of Hpo is critical for Hippo kinase activity. The Hippo C-terminal half promotes cytoplasmic localization and activity of Hippo. Conclusion: Dimerization and nucleocytoplasmic translocation of Hippo are crucial for its biological function. Significance: Dimerization and cytoplasmic localization regulate Hippo activity.

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Furthermore, two studies identified Tao-1, a STE20 family protein kinase as a positive regulator of the Hippo pathway, possibly by directly phosphorylating and activating the Hpo kinase (Boggiano et al, 2011;Poon et al, 2011). In addition, homodimerization was also found to regulate Hpo kinase activity (Jin et al, 2012). Another exciting finding is that accumulation of F-actin in vivo by loss of actin capping proteins or expression of active formin leads to tissue over growth due to inhibition of the Hippo pathway (Fernández et al, 2011;Sansores-Garcia et al, 2011).…”

Germinal center kinases in immune regulation

“…17 We and others have shown that both kinase domain mediated dimerization and C-terminus-mediated dimerization are required for the activation of Hpo or MST1. 17,51 Structural information of the full-length MST1/ 2 and complexes with Sav, RapL, Daxx and PRX-I should provide an in-depth mechanistic dissection of the MST1/2 activation and regulation, which together with mutational analysis would strongly support further functional studies of the MST1/2 signaling pathway.…”

Homeostatic Control of Hpo/MST Kinase Activity through Autophosphorylation-Dependent Recruitment of the STRIPAK PP2A Phosphatase Complex

“…When overexpressed in cells, MST1/2 forms homodimers with elevated kinase activity, suggesting that homodimerization per se is sufficient to trigger autoactivation by trans-autophosphorylation (Creasy et al, 1996; Ni et al, 2013; Praskova et al, 2004). Autoactivation of Hpo/MST requires dimerization elements in both the N-terminal kinase domain and the C-terminal SARAH ( Sa lvador- Ra ssf- H po) domain, as mutations abolishing either the N- or the C-terminal dimerization domain strongly compromise autophosphorylation (Deng et al, 2013; Jin et al, 2012; Ni et al, 2013). SAV1 promotes MST dimerization and activation by forming heterotetramers containing two MST and two SAV1 subunits (Ni et al, 2013).…”