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STRIPAK integrates upstream signals to initiate the Hippo kinase cascade.

The Hippo pathway plays a critical role in development, tissue homeostasis and organ size; its dysregulation contributes to human diseases. Although MST1/2 and the MAP4Ks are well known as the Hippo kinases, a major open question is how these kinases are regulated by upstream signals. Here we report that STRIPAK integrates upstream signals to control the activities of MST1/2 and the MAP4Ks, thus initiating Hippo signalling. STRIPAK also serves as a master regulator for the STE20 family kinases. Following serum or lysophosphatidic acid stimulation, active RhoA binds and dissociates rhophilin and NF2/Kibra from STRIPAK, thereby inducing the association and dephosphorylation of MST1/2 and MAP4Ks by the STRIPAK phosphatase catalytic subunit PP2AC. Rhophilin suppresses cancer cell growth by activating the Hippo pathway. Our study reveals a RhoA-rhophilin-NF2/Kibra-STRIPAK signalling axis in Hippo regulation, thus addressing the key question of how Hippo signalling is initiated and suggesting a broad and active role for STRIPAK in cellular signalling.

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Identification of crucial miRNAs and lncRNAs for ossification of ligamentum flavum.

The present study aimed to screen crucial micro (mi)RNAs and long non‑coding (lnc)RNAs involved in the development of ossification of ligamentum flavum (OLF) based on the miRNA‑mRNA and lncRNA‑miRNA‑mRNA competing endogenous (ce)RNA regulatory network analyses, which are rarely reported. The differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs) and differentially expressed miRNAs (DEMs) between 4 OLF and 4 healthy controls were identified using two microarray datasets GSE106253 and GSE106256 collected from the Gene Expression Omnibus database. A protein‑protein interaction (PPI) network was constructed, followed by calculation of topological characteristics and sub‑module analysis in order to obtain hub DEGs. The miRNA‑mRNA and lncRNA‑miRNA networks that were established based on their interaction pairs, obtained from miRwalk and starBase databases, respectively, were integrated to form the ceRNA network. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The present study screened 828 DEGs, 119 DELs and 81 DEMs between OLF and controls. PPI network and module analyses identified interleukin (IL)10, adenylate cyclase (ADCY)5, suppressor of cytokine signaling (SOCS)3, G protein subunit gamma (GNG) 4, collagen type II α 1 chain (COL2A1) and collagen type XIII α 1 chain (COL13A1) as hub genes. The miRNA‑mRNA network analysis demonstrated IL10 could be regulated by miR‑210‑3p, while COL13A1 and COL2A1 could be modulated by miR‑329‑3p and miR‑222‑5p, respectively. lncRNA‑miRNA‑mRNA ceRNA network analysis identified that small nucleolar RNA host gene 16‑hsa‑miR‑196a‑5p‑SOCS3, ankyrin repeat and SOCS box containing 16‑AS1‑hsa‑miR‑379‑5p‑GNG4, nuclear enriched abundant transcript 1‑has‑miR‑181b‑5p‑ADCY5, rhophilin 1‑AS1‑hsa‑miR‑299‑3p‑WNT7B interaction axes may be crucial. DAVID analysis predicted IL10, ADCY5, GNG4 and SOCS3 were involved in 'adaptive immune response', 'Chemokine signaling pathway' and 'regulation of apoptosis' processes, while COL2A1, COL13A1 and WNT7B may be ossification related. In conclusion, the identification of these crucial miRNAs and lncRNAs may be conducive for explaining the pathogenesis of OLF and provide certain natural, endogenous and nontoxic drug targets for the treatment of OLF.

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