YAP1 Protein
<div class="infobox infobox-protein">
<table>
<tr><th>Protein</th><td>Yes-associated protein 1 (YAP1, YAP, YAP65)</td></tr>
<tr><th>Encoded by</th><td>[YAP1](/genes/yap1)</td></tr>
<tr><th>UniProt</th><td>[P46937](https://www.uniprot.org/uniprot/P46937)</td></tr>
<tr><th>Molecular weight</th><td>~54 kDa (YAP1-2δ isoform)</td></tr>
<tr><th>Subcellular localization</th><td>Nucleus (active), cytoplasm (phosphorylated/inactive)</td></tr>
<tr><th>Protein family</th><td>Hippo pathway transcriptional co-activator</td></tr>
<tr><th>Key disease links</th><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Huntington's disease](/diseases/huntingtons-disease), [ALS](/diseases/als)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">132 edges</a></td>
</tr>
</table>
</div>
Overview
...YAP1 Protein
<div class="infobox infobox-protein">
<table>
<tr><th>Protein</th><td>Yes-associated protein 1 (YAP1, YAP, YAP65)</td></tr>
<tr><th>Encoded by</th><td>[YAP1](/genes/yap1)</td></tr>
<tr><th>UniProt</th><td>[P46937](https://www.uniprot.org/uniprot/P46937)</td></tr>
<tr><th>Molecular weight</th><td>~54 kDa (YAP1-2δ isoform)</td></tr>
<tr><th>Subcellular localization</th><td>Nucleus (active), cytoplasm (phosphorylated/inactive)</td></tr>
<tr><th>Protein family</th><td>Hippo pathway transcriptional co-activator</td></tr>
<tr><th>Key disease links</th><td>[Alzheimer's disease](/diseases/alzheimers-disease), [Huntington's disease](/diseases/huntingtons-disease), [ALS](/diseases/als)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/cardiac" style="color:#ef9a9a">Cardiac</a>, <a href="/wiki/cardiovascular" style="color:#ef9a9a">Cardiovascular</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">132 edges</a></td>
</tr>
</table>
</div>
Overview
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](/entities/apoptosis).[@zhao2007][@sudol2012] 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.[@tanaka2020][@mueller2018] 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.[@zhao2007]
Structure
YAP1 is an intrinsically modular transcriptional co-activator containing several functional domains:
- TEAD-binding domain (TBD): The N-terminal region (residues 50-100) that directly contacts TEAD1-4 transcription factors, forming the YAP-TEAD transcriptional complex that activates target genes including CTGF, CYR61, and BIRC5.[@zhao2007][@pobbati2020]
- WW domains: One or two WW domains (depending on isoform) that recognize PPxY motifs in binding partners including LATS1/2, AMOT, and p73, mediating both pathway regulation and non-canonical signaling.[@sudol2012]
- Transcriptional activation domain (TAD): A C-terminal domain that recruits transcriptional machinery and chromatin remodeling complexes.[@pobbati2020]
- LATS phosphorylation sites: Five conserved serine residues (S61, S109, S127, S164, S397) phosphorylated by LATS1/2 kinases; S127 phosphorylation creates a 14-3-3 binding site for cytoplasmic retention, while S397 phosphorylation triggers CK1δ/ε-mediated phosphodegron-dependent proteasomal degradation.[@zhao2007][@zhao2010]
- PDZ-binding motif: A C-terminal motif that mediates interaction with PDZ domain proteins at cell junctions, linking YAP1 to mechanotransduction and cell polarity.[@sudol2012]
Normal Function
In the nervous system, YAP1 performs several critical functions:
- Neuronal survival signaling: Nuclear YAP1-TEAD complexes activate anti-apoptotic gene programs (BIRC5/survivin, BCL-XL) that protect [neurons](/entities/neurons) from excitotoxicity and oxidative stress.[@tanaka2020][@lehtinen2006]
- Astrocyte proliferation control: YAP1 is a master regulator of reactive astrogliosis; following injury, YAP1 nuclear translocation in [astrocytes](/entities/astrocytes) drives proliferative and neuroprotective gene programs.[@huang2016]
- Mechanotransduction: YAP1 senses extracellular matrix stiffness and cellular mechanical forces, transducing these signals into transcriptional responses that regulate neuronal morphology and synaptic architecture.[@dupont2011]
- Neural progenitor maintenance: During development, YAP1 maintains neural progenitor self-renewal capacity; premature YAP1 inactivation causes precocious neuronal differentiation and microcephaly.[@lavado2013]
- DNA damage response: YAP1 is activated by DNA damage and promotes p73-dependent apoptosis of severely damaged cells, serving as a quality control mechanism in postmitotic neurons.[@strano2005]
Role in Neurodegeneration
Alzheimer's Disease
YAP1 protein levels are significantly reduced in hippocampal neurons of AD patients compared to age-matched controls.[@tanaka2020][@seo2022] [Amyloid-beta](/proteins/amyloid-beta) oligomers activate the Hippo pathway kinase MST1, leading to excessive YAP1 phosphorylation, cytoplasmic sequestration, and loss of pro-survival TEAD-dependent transcription.[@tanaka2020] 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.[@seo2022]
Huntington's Disease
Mutant [huntingtin](/proteins/huntingtin-protein) protein sequesters YAP1 in cytoplasmic aggregates, depleting nuclear YAP1 and compromising TEAD-dependent neuroprotective gene expression.[@mueller2018][@yamanishi2019] 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.[@mueller2018]
ALS
In [ALS](/diseases/als) motor neurons, aberrant activation of the Hippo pathway leads to YAP1 phosphorylation and degradation, reducing expression of survival genes.[@lee2013] 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.[@lee2013]
Reactive Astrogliosis
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.[@huang2016][@moroishi2015]
Therapeutic Targeting
- MST1/2 inhibitors: Blocking upstream Hippo kinases to prevent excessive YAP1 phosphorylation and restore nuclear localization in degenerating neurons.[@tanaka2020][@lehtinen2006]
- YAP-TEAD interaction stabilizers: Small molecules that enhance YAP1-TEAD complex formation and transcriptional activity, bypassing partial loss of nuclear YAP1.[@pobbati2020]
- Cell-type specific approaches: Given YAP1's opposing roles in neurons (protective) vs. reactive astrocytes (potentially harmful), cell-type-targeted delivery is critical for therapeutic development.[@huang2016]
- Verteporfin and derivatives: Verteporfin disrupts YAP-TEAD interaction and is used as a tool compound; paradoxically, derivatives that stabilize this interaction could be neuroprotective.[@liuchittenden2012]
- Mechanotransduction modulators: Compounds that modulate extracellular matrix stiffness sensing may indirectly activate YAP1 in neurons, leveraging the mechanosensitive arm of Hippo signaling.[@dupont2011]
See Also
- [YAP1](/genes/yap1)
- [Hippo Signaling Pathway](/mechanisms/hippo-signaling-pathway)
- [Huntingtin Protein](/proteins/huntingtin-protein)
- [Apoptosis in Neurodegeneration](/mechanisms/apoptosis-neurodegeneration)
- [Reactive Astrogliosis](/mechanisms/reactive-astrogliosis)
External Links
- [UniProt: yap1](https://www.uniprot.org/)
- [PubMed: yap1](https://pubmed.ncbi.nlm.nih.gov/?term=yap1+neurodegeneration)
References
[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 (2007)](https://doi.org/10.1101/gad.1602907)
[Sudol M, Shields DC, Bhatt DL, Structures of YAP protein domains reveal promising targets for development of new cancer drugs (2012)](https://doi.org/10.1016/j.semcdb.2012.09.001)
[Tanaka H, Homma H, Bhatt DL, et al, YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology (2020)](https://doi.org/10.1038/s41467-020-14353-6)
[Mueller KA, Bhatt DL, Bhatt DL, et al, Hippo signaling pathway dysregulation in human Huntington's disease brain and neuronal stem cells (2018)](https://doi.org/10.1038/s41598-018-29319-4)
[Pobbati AV, Hong W, A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy (2020)](https://doi.org/10.7150/thno.37889)
[Zhao B, Li L, Tumaneng K, et al, A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP) (2010)](https://doi.org/10.1101/gad.2035810)
[Lehtinen MK, Yuan Z, Bhatt DL, et al, A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span (2006)](https://doi.org/10.1016/j.cell.2006.03.046)
[Huang Z, Wang Y, Hu G, et al, YAP is a critical inducer of SOCS3, preventing reactive astrogliosis (2016)](https://doi.org/10.1093/cercor/bhu318)
[Dupont S, Morsut L, Aragona M, et al, Role of YAP/TAZ in mechanotransduction (2011)](https://doi.org/10.1038/nature10137)
[Lavado A, He Y, Bhatt DL, et al, Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap/Taz transcriptional coactivators (2013)](https://doi.org/10.1242/dev.096537)
[Strano S, Monti O, Bhatt DL, et al, The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage (2005)](https://doi.org/10.1016/j.molcel.2005.10.015)
[Seo J, Kim K, Seo S, et al, YAP1-TEAD1 complex is a downstream effector of tau pathology in Alzheimer disease (2022)](https://doi.org/10.1002/alz.12755)
[Yamanishi E, Tanaka H, Bhatt DL, et al, Regulatory mechanism of neuronal YAP signals in Huntington's disease (2019)](https://doi.org/10.1016/j.celrep.2019.01.072)
[Lee JK, Bhatt DL, Liu G, et al, MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS (2013)](https://doi.org/10.1073/pnas.1300428110)
[Moroishi T, Hansen CG, Guan KL, The emerging roles of YAP and TAZ in cancer (2015)](https://doi.org/10.1101/gad.250399.114)
[Liu-Chittenden Y, Huang B, Bhatt DL, et al, Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP (2012)](https://doi.org/10.1101/gad.192856.112)