Abstract
The MST-LATS kinase cascade is central to the Hippo pathway that controls tissue homeostasis, development, and organ size. The PP2A complex STRIPAKSLMAP blocks MST1/2 activation. The GCKIII family kinases associate with STRIPAK, but the functions of these phosphatase-associated kinases remain elusive. We previously showed that the scaffolding protein SAV1 promotes Hippo signaling by counteracting STRIPAK (Bae et al., 2017). Here, we show that the GCKIII kinase STK25 promotes STRIPAK-mediated inhibition of MST2 in human cells. Depletion of STK25 enhances MST2 activation without affecting the integrity of STRIPAKSLMAP. STK25 directly phosphorylates SAV1 and diminishes the ability of SAV1 to inhibit STRIPAK. Thus, STK25 as the kinase component of STRIPAK can inhibit the function of the STRIPAK inhibitor SAV1. This mutual antagonism between STRIPAK and SAV1 controls the initiation of Hippo signaling.
Highlights
The Hippo pathway is critical for organ size control, tissue homeostasis, development, and tumor suppression by restricting cell proliferation and promoting apoptosis (Harvey and Tapon, 2007; Pan, 2010; Johnson and Halder, 2014; Yu et al, 2015; Fu et al, 2017; Misra and Irvine, 2018)
Overexpression of STK25, but not overexpression of MST3 or MST4, decreased MST2 pT180 (Figure 1—figure supplement 1B). These results suggest that, among the three GCKIII kinases, only STK25 is involved in suppressing MST2 activation
We have previously shown that the STRIPAKSLMAP complex binds the phosphorylated MST2 linker and reverses MST1/2 activation in a feedback mechanism (Bae et al, 2017)
Summary
The Hippo pathway is critical for organ size control, tissue homeostasis, development, and tumor suppression by restricting cell proliferation and promoting apoptosis (Harvey and Tapon, 2007; Pan, 2010; Johnson and Halder, 2014; Yu et al, 2015; Fu et al, 2017; Misra and Irvine, 2018). Dysregulation of the Hippo pathway is linked to tumor initiation and progression in flies, mice, and humans (Pan, 2010; Halder and Johnson, 2011; Yu and Guan, 2013; Yu et al, 2015). When the Hippo pathway is on, the MST1/2–SAV1 complexes phosphorylate and activate the LATS1/2–MOB1 complexes (Chan et al, 2005; Praskova et al, 2008). The YAP/TAZ–TEAD transcription factors induce the expression of Hippo-target genes to enable cell proliferation and survival (Zhao et al, 2008; Luo, 2010)
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