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. 2021 Jan 12;12(1):79. doi: 10.1038/s41419-021-03395-3

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — The core components of the Hippo pathway encompass MST1/2 and LATS1/2, whereas YAP/TAZ are two major effectors of this pathway. Traditionally, upstream signals turn on the Hippo pathway by phosphorylating and activating MST1/2 as well as the scaffold protein SAV1, followed by phosphorylation and activation of LATS1/2 and the scaffold protein MOB1, thereby preventing YAP/TAZ from translocating to the nucleus and initiating gene expression via binding to TEADs. VGLL4, a transcriptional co-repressor, competes with YAP/TAZ for TEADs binding. Instead, phosphorylated YAP/TAZ are isolated in the cytoplasm through interaction with protein 14-3-3 or experience ubiquitylation and degradation. Expanded Hippo pathway encompasses MAP4Ks as well as NDR1/2. MAP4Ks function similarly as MST1/2, performing activating phosphorylation of LATS1/2 and/or NDR1/2, consequently leading to the inhibition of downstream YAP/TAZ via LATS1/2- or NDR1/2-regulated phosphorylation. The complex of YAP/TAZ and TEADs can both directly enhance the function of LATS2 and indirectly stimulate LATS1/2 expression via NF2, which constitute a feedback loop. Independent of the upstream kinases, YAP/TAZ may be directly sequestered at cell junctions via interacting with PTPN14, AMOTs, and α-catenin. NF2, Kibra, RASSF1A, and TAO-K stimulated by upstream stimuli, may phosphorylate and activate MST1/2 and/or MAP4Ks. GPCRs may inhibit and enhance LATS1/2 depending on the types of receptors. Arrows, blunt ends, and dotted lines indicate activation, inhibition, and possible regulatory effect, respectively. MST1/2, mammalian sterile 20-like 1/2; SAV1, salvador; LATS1/2, large tumour suppressor homologue 1/2; MOB1A/B, MOB kinase activator 1A/B; YAP, yes-associated protein; TAZ, transcriptional co-activator with PDZ-binding motif; NF2, neurofibromin2/Merlin; TAO-K, thousand and one amino acid protein kinase; MAP4Ks, mitogen-activated protein kinase kinase kinase kinase; TEAD, transcriptional enhancer associated domain; VGLL4, vestigial-like family member 4; PTPN14, protein tyrosine phosphatase non-receptor type 14; AMOT, angiomotin.