The STRIPAK Complex Regulates the Hippo Kinase Cascade

Dysregulation of the Hippo pathway, which centers on the MST1/2 and MAP4K-family kinases, can contribute to cancer development. Although much of this complex pathway has been well characterized, some areas remain to be elucidated, particularly how MST1/2 and MAP4Ks are regulated by signals upstream in the pathway. Chen and colleagues found evidence for a previously unknown role of the striatin-interacting phosphatase and kinase (STRIPAK) complex, which had previously been shown to inhibit MST1/2 in some contexts, in integrating these upstream signals to trigger Hippo signaling. In vitro experiments demonstrated that the mitogen lysophosphatidic acid (LPA) promotes interactions between PPA2AC (STRIPAK's catalytic subunit) and STRIP (a core STRIPAK component), stimulating interactions between PPA2AC and MAP4Ks, leading to MAP4K inhibition. Further experiments confirmed that a functional STRIPAK complex is required for the observed inhibition of MST1/2 and MAP4Ks by LPA. Additionally, RHOA, a small GTPase previously demonstrated to mediate LPA's effects on the Hippo pathway, was also shown to inhibit MST1 and MAP4K activity, acting as a mediator between LPA and STRIPAK. Deeper investigation revealed that KIBRA and NF2, membrane-associated proteins known to activate the Hippo pathway, lie downstream of RHOA and regulate the interaction between MAP4K and STRIPAK. Rhophilin, a RHOA-binding protein with no apparent enzymatic activity, mediated the interaction between KIBRA and NF2. Finally, STRIPAK physically interacted with and regulated many members of the STE20 kinase family, which often act at the top of kinase cascades. Collectively, the results presented in this study provide deep and highly detailed insight into the regulation of the Hippo signaling pathway, a key player in many cancers.

Chen R, Xie R, Meng Z, Ma S, and Guan KL. STRIPAK integrates upstream signals to initiate the Hippo kinase cascade. Nat Cell Biol 2019;21:1565–77.

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