Abstract
Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment.
Highlights
The Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation and apoptosis, and its alterations participate to cancer development
The best studied role of YAP in skeletal muscle is as a regulator of myoblast proliferation and terminal differentiation
Several studies together demonstrate that YAP and transcriptional activator with PDZ binding motif (TAZ) activity are increased as satellite cells/myoblasts proliferate and that further increasing their activity, by over-expression of mutant YAP/TAZ proteins that cannot be inhibited by large tumor suppressor 1/2 (LATS1/2), results in an enhanced rate of myoblast proliferation [8,9,19]
Summary
The Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation and apoptosis, and its alterations participate to cancer development. Yes-associated protein 1 (YAP or YAP1) is a downstream target of the Hippo pathway and acts as a transcription co-activator [1]. YAP can be down-regulated through phosphorylation by the large tumor suppressor 1/2 (LATS1/2) kinase [2]. Phosphorylated YAP interacts with cytoskeletal proteins and is maintained in the cytoplasm. Non-phosphorylated YAP translocates to the nucleus where it exerts its regulatory function on many transcription factors such as TEAD family, being TEAD and YAP transcriptional coactivators in most of genomic loci [3]. Important target genes of YAP are Cyclin D1, Birc, and myogenic transcription factor Myf5 [4]
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