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  • It has been reported that the pathway upstream of

    2022-08-04

    It has been reported that the pathway upstream of YAP phosphorylation is operative in a tissue or context-specific manner. LPA or S1P bound to their corresponding membrane GPCRs and act through Rho GTPases to activate YAP/TAZ [11]. Consistently, another report showed that activation of PAR1 (a GPCR) that couple to G12/13 triggers the activation of Rho GTPase, which works through the A-1155463 cytoskeleton to inhibit LATS1/2 kinase, leading to eventual YAP/TAZ dephosphorylation, nuclear localization, and gene expression [12]. However, the signaling mechanism linking Gαs-coupled GPCRs to LATS activation was not elucidated. A recent study showed that cyclic adenosine monophosphate (cAMP), a second messenger downstream from Gαs-coupled receptors, acts through protein kinase A (PKA) and Rho GTPases to stimulate LATS kinases and YAP phosphorylation [24]. These findings suggest that the activity of YAP can be positively or negatively modulated by a wide range of extracellular signals via GPCRs in a manner dependent on which G proteins is stimulated. As the results shown in Fig. 3, we found that DHA inactivates YAP by inducing phosphorylation dependent on FFAR1, FFAR4, Gαs and PKA. In addition, it is well known that SAV1 facilitates MST1/2 kinases to phosphorylate and activate LATS1/2, in turn, phosphorylate and inactivate the transcriptional coactivator YAP. However, previous studies showed that extracellular ligands bound to their corresponding membrane GPCRs and modulate YAP activity in LATS-dependent or LATS-independent manner [11,25]. The data in this paper clearly showed that DHA increases YAP phosphorylation dependent on the canonical Hippo pathway. We found that a reduction of YAP phosphorylation when the protein level of LATS1 and MST1 have been knockdown and DHA-induced YAP phosphorylation was reversed by both the LATS1 and MST1 siRNAs. Moreover, we can also found that both the phosphorylation of MST1 and LATS1 increased following DHA treatment, further proved DHA inactivates YAP through FFAR1 and FFAR4 in the canonical Hippo pathway-dependent manner (Fig. 3A–D). In conclusion, our findings provide a novel insight into how DHA modulates androgen-independent prostate cancer cells proliferation.
    Conflicts of interest
    Funding This work was supported by the National Natural Science Foundation of China (No.81670558; 81800542), and the Science & Technology Development Fund of Tianjin Education Commission for Higher Education (No.2017KJ221).
    Acknowledgements
    Although type-2 diabetes mellitus (T2DM) is not a recent disease, with a history dated back to the middle of the sixth century, its prevalence is rising every day. The disease is a progressive cluster of metabolic disturbances characterized by chronic hyperglycemia arising from insufficient pancreatic insulin secretion and resistance to insulin action or a combination of both. As for complications, T2DM is one of the primary causes of renal injury, eye problems, amputations and hospitalizations and is associated with high rates of morbidity and mortality. Currently, T2DM is a global public health burden affecting more than 367 million people worldwide. According to the World Health Organization (WHO), the number is expected to reach 557 million by the year 2030. An efficient management of T2DM comprises of several stages. Typically, the first step could be achieved through lifestyle modifications including healthy diet and exercise. However, when changing lifestyle is not sufficient, pharmacotherapy is required. A variety of oral hypoglycemic medications were developed either to increase insulin secretion (secretagogues), enhance insulin action (insulin sensitizers), or slow glucose absorption. Examples of insulin sensitizers include metformin and thiazolidinediones (TZDs), while oral sulfonylureas and meglitinides are prescribed as insulin secretagogues. Since introduced in the late 90s, TZDs are considered as potent agonists of peroxisome proliferator-activated receptors (PPARs). The latter represent a group of nuclear hormone receptors responsible for the expression of a number of genes concerning with glucose and fat metabolism. The PPARs are abundant in the key target tissues for insulin action including skeletal muscles, adipose tissues, and liver. Out of the three distinct PPAR isoforms, PPAR-α, -β and -γ, the activation of PPAR-γ has the major role in regulating glucose homeostasis, inflammatory responses, cellular differentiation, and apoptosis.