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

• Published in: Cell reports (Cambridge) 2017-12, Vol.21 (12), p.3612-3623
• Main Authors: Zheng, Yonggang, Liu, Bo, Wang, Li, Lei, Huiyan, Pulgar Prieto, Katiuska Daniela, Pan, Duojia
• Format: Article
• Language: English
• Subjects: Animals; autophosphorylation; Binding Sites; Drosophila; Drosophila Proteins - chemistry; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; HEK293 Cells; HeLa Cells; Hippo signaling; Homeostasis; Hpo; Humans; Intracellular Signaling Peptides and Proteins - chemistry; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; MST1/2; Phosphorylation; PP2A; Protein Binding; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; SLMAP; STRIPAK; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.11.076

The Hippo pathway controls organ size and tissue homeostasis through a kinase cascade leading from the Ste20-like kinase Hpo (MST1/2 in mammals) to the transcriptional coactivator Yki (YAP/TAZ in mammals). Whereas previous studies have uncovered positive and negative regulators of Hpo/MST, how they are integrated to maintain signaling homeostasis remains poorly understood. Here, we identify a self-restricting mechanism whereby autophosphorylation of an unstructured linker in Hpo/MST creates docking sites for the STRIPAK PP2A phosphatase complex to inactivate Hpo/MST. Mutation of the phospho-dependent docking sites in Hpo/MST or deletion of Slmap, the STRIPAK subunit recognizing these docking sites, results in constitutive activation of Hpo/MST in both Drosophila and mammalian cells. In contrast, autophosphorylation of the Hpo/MST linker at distinct sites is known to recruit Mats/MOB1 to facilitate Hippo signaling. Thus, multisite autophosphorylation of Hpo/MST linker provides an evolutionarily conserved built-in molecular platform to maintain signaling homeostasis by coupling antagonistic signaling activities. [Display omitted] •The Hpo/MST linker contains inhibitory autophosphorylation sites•The autoinhibitory sites of Hpo/MST bind Slmap in a phospho-dependent manner•Slmap recruits the STRIPAK PP2A complex to inactivate Hpo/MST The Hippo pathway was named after the Ste20-like kinase Hpo/MST, but how its activity is regulated remains unclear. Zheng et al. identify a self-restricting mechanism whereby autophosphorylation of an unstructured linker in Hpo/MST creates docking sites for the STRIPAK PP2A phosphatase complex to inactivate Hpo/MST in both Drosophila and mammals.