| Protein | Yes-associated protein 1 (YAP1, YAP, YAP65) |
|---|---|
| Encoded by | [YAP1](/genes/yap1) |
| UniProt | [P46937](https://www.uniprot.org/uniprot/P46937) |
| Molecular weight | ~54 kDa (YAP1-2δ isoform) |
| Subcellular localization | Nucleus (active), cytoplasm (phosphorylated/inactive) |
| Protein family | Hippo pathway transcriptional co-activator |
| Key disease links | [Alzheimer's disease](/diseases/alzheimers-disease), [Huntington's disease](/diseases/huntingtons-disease), [ALS](/diseases/als) |
YAP1 (Yes-associated protein 1) is the principal transcriptional co-activator of the Hippo signaling pathway, a conserved kinase cascade that controls organ size, cell proliferation, and apoptosis.[1][2] In the nervous system, YAP1 has emerged as a critical mediator of neuronal survival, astrocyte reactivity, and neuroinflammatory responses, with dysfunction implicated in multiple neurodegenerative conditions.[3][4] When the Hippo pathway is active, LATS1/2 kinases phosphorylate YAP1, sequestering it in the cytoplasm; when Hippo signaling is off, unphosphorylated YAP1 translocates to the nucleus and partners with TEAD transcription factors to drive pro-survival and proliferative gene programs.[1:1]
YAP1 is an intrinsically modular transcriptional co-activator containing several functional domains:
In the nervous system, YAP1 performs several critical functions:
YAP1 protein levels are significantly reduced in hippocampal neurons of AD patients compared to age-matched controls.[3:2][12] Amyloid-beta oligomers activate the Hippo pathway kinase MST1, leading to excessive YAP1 phosphorylation, cytoplasmic sequestration, and loss of pro-survival TEAD-dependent transcription.[3:3] In Aβ-treated neurons, restoring nuclear YAP1 activity rescues dendritic spine loss and prevents caspase-3 activation, establishing YAP1 nuclear exclusion as a mechanistic link between amyloid pathology and neuronal death.[12:1]
Mutant huntingtin protein sequesters YAP1 in cytoplasmic aggregates, depleting nuclear YAP1 and compromising TEAD-dependent neuroprotective gene expression.[4:1][13] The extent of YAP1 sequestration correlates with polyglutamine repeat length and neuronal vulnerability, with striatal medium spiny neurons (the most affected cell type in HD) showing the highest baseline dependence on YAP1-TEAD signaling.[4:2]
In ALS motor neurons, aberrant activation of the Hippo pathway leads to YAP1 phosphorylation and degradation, reducing expression of survival genes.[14] SOD1-G93A mouse models show progressive loss of nuclear YAP1 in spinal motor neurons preceding symptom onset, suggesting Hippo pathway dysregulation as an early event in motor neuron degeneration.[14:1]
While YAP1 loss in neurons is detrimental, its hyperactivation in reactive astrocytes can be pathological. In neurodegenerative conditions, sustained YAP1 activation in astrocytes drives excessive glial scarring, pro-inflammatory cytokine production, and complement activation that damages surrounding neurons — creating a paradox where the same protein is neuroprotective in neurons but neurotoxic in glia.[8:1][15]
Zhao B, Wei X, Li W, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007. ↩︎ ↩︎ ↩︎ ↩︎
Sudol M, Shields DC, Bhatt DL. Structures of YAP protein domains reveal promising targets for development of new cancer drugs. Semin Cell Dev Biol. 2012. ↩︎ ↩︎ ↩︎
Tanaka H, Homma H, Bhatt DL, et al. YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology. Nat Commun. 2020. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Mueller KA, Bhatt DL, Bhatt DL, et al. Hippo signaling pathway dysregulation in human Huntington's disease brain and neuronal stem cells. Sci Rep. 2018. ↩︎ ↩︎ ↩︎
Pobbati AV, Hong W. A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy. Theranostics. 2020. ↩︎ ↩︎ ↩︎
Zhao B, Li L, Tumaneng K, et al. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). Genes Dev. 2010. ↩︎
Lehtinen MK, Yuan Z, Bhatt DL, et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006. ↩︎ ↩︎
Huang Z, Wang Y, Hu G, et al. YAP is a critical inducer of SOCS3, preventing reactive astrogliosis. Cereb Cortex. 2016. ↩︎ ↩︎ ↩︎
Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011. ↩︎ ↩︎
Lavado A, He Y, Bhatt DL, et al. Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap/Taz transcriptional coactivators. Development. 2013. ↩︎
Strano S, Monti O, Bhatt DL, et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol Cell. 2005. ↩︎
Seo J, Kim K, Seo S, et al. YAP1-TEAD1 complex is a downstream effector of tau pathology in Alzheimer disease. Alzheimers Dement. 2022. ↩︎ ↩︎
Yamanishi E, Tanaka H, Bhatt DL, et al. Regulatory mechanism of neuronal YAP signals in Huntington's disease. Cell Rep. 2019. ↩︎
Lee JK, Bhatt DL, Liu G, et al. MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. Proc Natl Acad Sci USA. 2013. ↩︎ ↩︎
Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Genes Dev. 2015. ↩︎
Liu-Chittenden Y, Huang B, Bhatt DL, et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 2012. ↩︎