DNA binding partners of YAP/TAZ

Abstract

Hippo signaling plays critical roles in regulation of tissue homeostasis, organ size, and tumorigenesis by inhibiting YES-associated protein (YAP) and PDZ-binding protein TAZ through MST1/2 and LATS1/2 pathway. It is also engaged in cross-talk with various other signaling pathways, including WNT, BMPs, Notch, GPCRs, and Hedgehog to further modulate activities of YAP/TAZ. Because YAP and TAZ are transcriptional coactivators that lack DNA-binding activity, both proteins must interact with DNA-binding transcription factors to regulate target gene’s expression. To activate target genes involved in cell proliferation, TEAD family members are major DNA-binding partners of YAP/TAZ. Accordingly, YAP/TAZ were originally classified as oncogenes. However, YAP might also play tumor-suppressing role. For example, YAP can bind to DNA-binding tumor suppressors including RUNXs and p73. Thus, YAP might act either as an oncogene or tumor suppressor depending on its binding partners. Here, we summarize roles of YAP depending on its DNA-binding partners and discuss context-dependent functions of YAP/TAZ.

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…For example, NF2/Merlin-orchestrated palmitoylation of TEAD independent of YAP/TAZ is required to stabilize and activate TEAD in response to cell contact [99]. In addition to TEAD, there are multiple and frequently co-expressed transcription factors that can partner with YAP and/or TAZ [28], but little is known about the mechanisms and factors that regulate the target specificity of YAP/TAZ-driven co-activation.…”

“…Among typical YAP/TAZ targets are several secretory factors, including amphiregulin, connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61), which are important in stromal interactions and niche formation of cancer metastasis [18][19][20][21][22].There is ample and rapidly growing literature on the mechanisms of YAP/TAZ regulation, particularly by the Hippo signaling pathway, which prohibits organ overgrowth through the regulation of cell proliferation and cell survival during normal development. Recent excellent and comprehensive reviews summarize this wealth of published information from different angles: from a protein structural perspective [23,24]; from the angle of tissue mechanics, microenvironment and cytoskeleton interactions [25][26][27]; from the aspect of DNA-binding protein partners of YAP/TAZ [28,29] and in the context of normal development [30]; specific cancers (i.e., of the breast [31], lung [32] liver [33], prostate [34], pancreas [35] and various pediatric cancers [36]) and other chronic and neurodegenerative diseases [37,38].The adaptation to microenvironments of different tissue architecture plays a particularly important role in bone cancers which tend to metastasize through the hematogenous route and home primarily to bone and lungs, which are organs of completely different stiffness, extracellular matrix composition and oxygen supply. It is therefore not unexpected that the YAP/TAZ signaling pathway is prominently involved in bone cancer pathogenesis and metastatic spread.…”

“…There is ample and rapidly growing literature on the mechanisms of YAP/TAZ regulation, particularly by the Hippo signaling pathway, which prohibits organ overgrowth through the regulation of cell proliferation and cell survival during normal development. Recent excellent and comprehensive reviews summarize this wealth of published information from different angles: from a protein structural perspective [23,24]; from the angle of tissue mechanics, microenvironment and cytoskeleton interactions [25][26][27]; from the aspect of DNA-binding protein partners of YAP/TAZ [28,29] and in the context of normal development [30]; specific cancers (i.e., of the breast [31], lung [32] liver [33], prostate [34], pancreas [35] and various pediatric cancers [36]) and other chronic and neurodegenerative diseases [37,38].…”

PnBA/PDMAA‐Based Iron‐Loaded Micropillars Allow for Discrete Cell Adhesion and Analysis of Actuation‐Related Molecular Responses

“…Among these complexes, the transcription enhancer factors bind the cotranscriptional activators TAZ and YAP in the nucleus, which are both downstream targets of the so‐called Hippo‐signaling pathway 38. The complex regulates the expression of genes relevant for cell proliferation 39.…”

Cell contact and Nf2/Merlin-dependent regulation of TEAD palmitoylation and activity

“…Mst1/2 (Mammalian Ste20like kinases 1/2) and MAP4Ks (Mitogen-activated protein kinase kinase kinase kinases) phosphorylate and activate the Lats1/2 kinases in response to a number of upstream signals (2)(3)(4)(5). In a growth permissive state, YAP/TAZ are translocated into the nucleus where they interact with various DNA binding transcription factors, especially TEADs (TEA domain family members), but also p73, Runx2, and ERBB4 (6). Because YAP/TAZ lack the DNA binding domain, the transcription of their downstream target genes is determined by DNA binding transcription factors.…”