15 When the Hippo pathway is turned off, dephosphorylated YAP/TAZ translocate into the nucleus and primarily bind with TEA domain family transcription factors (TEAD1–TEAD4 in mammals) to initiate expression of genes involved in the cell cycle, cell migration, or cell fate regulation ( Figure 1). Phosphorylated YAP/TAZ is sequestered in the cytoplasm by interacting with 14-3-3 14 and/or are degraded by the proteasome pathway. 12, 13 The physiologic output of this kinase cascade is the restricted activity of transcriptional co-activators YAP and TAZ. In addition to MST1/2, MAP4K family kinases also directly phosphorylate and activate LATS1/2 after cell stress. 6, 10, 11 The canonical core of the Hippo pathway in mammals is a kinase cascade in which MST1/2, together with its partner Salvador homolog 1 (SAV1), phosphorylates and activates LATS1/2 and adaptor protein, Mps one binder kinase activator-like 1A/1B (MOB1A/1B). 8, 9 Highly conserved in mammals, the Hippo pathway senses extracellular signals related to mechanical force, cell polarity, cell adhesion, and nutrient availability ( Figure 1). Mutations in genes encoding key components of Hippo signalling, such as Hpo ( MST1/2) and Warts ( LATS1/2), resulted in tissue overgrowth. The Hippo pathway was initially discovered as a modulator of cell proliferation in Drosophila. Particularly, we focus on the post-translational modification of Hippo pathway components, such as LATS1/2 and YAP/TAZ, and discuss the potential of Hippo signalling as a therapeutic target to stimulate endogenous cardiac repair. In this review, we summarize the role of the Hippo pathway in regulating heart development, homeostasis, and disease. 6, 7 In mammals, the Hippo pathway primarily consists of a core kinase cascade including mammalian STE20-like kinases 1/2 (MST1/2), large tumour suppressor 1/2 (LATS1/2), and two downstream transcriptional co-activators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). 4, 5 Originally discovered in Drosophila, the Hippo pathway is an evolutionarily conserved signalling pathway in organ size control and tumourigenesis. Recently, the Hippo pathway, which is a pivotal regulator of heart development and disease, has become a promising therapeutic target for heart regeneration. 3 Understanding the genetic mechanisms underlying cardiac renewal is critical for developing new therapeutic options for HF patients. pharmacologic treatment, heart transplantation, and left ventricular assist devices) are useful, they cannot meet the overwhelming need to reverse HF. 2 Although current treatment options (e.g. 1 When cardiac injury occurs, such as myocardial infarction (MI), the massive loss of CMs causes permanent functional damage and eventually results in heart failure (HF), which is the leading cause of death in the western world. The heart is one of the least regenerative organs in mammals, with a low rate of cardiomyocyte (CM) replacement. Hippo pathway, Heart development, Heart diseases, Post-translational modification, LATS1/2, YAP/TAZ 1.
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |