Type I and II Interferon are Associated with High Expression of the Hippo Pathway Family Members


The Hippo pathway plays a regulatory role on inflammation and cell death and proliferation. Here we described a relationship between Hippo pathway components and inflammation in healthy subjects. The plasma levels of cytokines and chemokines were used to define their inflammatory profile and classify them as normal, high and low producers of cytokines. Leukocytes from healthy subjects with inflammatory profile expressed the highest levels of MSTS1/MST2, SAV1, LATS1/LATS2, MOB1A/MOB1B and YAP genes. The group that overexpressed Hippo pathway-related genes secreted more IFN-ϒ and IFN-α2

The Hippo signaling pathway mediates tumor suppression and regulation of cell cycle and apoptosis. This pathway was first reported on Drosophila melanogaster, and it is also present and well-conserved in mammals [1], in which it is finely regulated by numerous signals – named as regulatory components – that mediate activation or inhibition, such as cell polarity, cell-cell contact, oxidative stress, and some hormones like insulin, glucagon, epinephrine, and follicle-stimulating hormone [2–9]. The main proteins that compose the Hippo signaling pathway are MST1/MST2 kinases (mammalian STE20-like protein kinase 1/2) and their adapter protein SAV1 (protein salvador homolog 1), LATS1/LATS2 kinases (large tumor suppressor kinase 1/2) and their adapter proteins MOB1A/MOB1B (MOB kinase activator 1A/1B), and the transcription coactivators YAP (yes-associated protein) and TAZ (tafazzin protein). Activation of this pathway is marked by regulatory signals that modulate phosphorylation of MST1/MST2 and SAV1. The active form of MST1/MST2 phosphorylates and activates LATS1/LATS2 and MOB1A/ MOB1B. The active form of LATS1/LATS2 phosphorylates and activates YAP and TAZ that interact with the protein complex 14.3.3 in cytoplasm; such interaction retains YAP and TAZ in the cytoplasm and degrades them by ubiquitination. When the Hippo pathway is inactive, YAP and TAZ migrate to the cell nucleus and mainly interact with the TEAD1-4 (TEA domain transcription) family transcription factors that activate expression of target genes that control cell proliferation and resistance to cell death, such as AXL (AXL receptor tyrosine kinase), BIRC5 (baculoviral IAP repeat containing 5), CTGF (connective tissue growth factor), CYR61 (cysteine-rich angiogenic inducer 61), FGF1 (fibroblast growth factor 1), GLI2 (GLI family zinc), IGFBP3 (insulin-like growth factor binding protein 3), and ITGB2 (integrin subunit β2).

Healthy subjects differentially express genes encoding Hippo pathway components. High expression levels of Hippo pathway genes are associated with high plasma levels of the cytokines IFN-ϒ and IFN-α2. High producers of inflammatory cytokines express the genes MST1, MST2, SAV1, LATS1, LATS2, MOB1A, MOB1B, and YAP more strongly than normal producers of cytokines.

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