YAP1 (P46937) - the Hippo pathway's transcriptional co-activator, and a KMT2A fusion partner from a completely different functional class

No three-dimensional model is available for this protein, so the map above is the whole picture. That is itself informative: AlphaFold does not model chains this long, and the parts that have been crystallised are held under the entries for the individual domains.

• YAP1/TEAD is the plausible drug axis in this entity rather than anything KMT2A-directed, but TEAD palmitoylation inhibitors have not been tested in KMT2A-rearranged sarcoma and YAP1's transactivation region is partly replaced in this allele, so on-target activity cannot be assumed from other YAP1-fusion tumours.
• YAP1 is a regeneration and wound-healing effector in normal liver, gut and heart, so sustained YAP1/TEAD blockade carries an essential-function toxicity risk that has nothing to do with this tumour.
• Naming YAP1 as the driver would move this entity out of the KMT2A franchise entirely - which is the right scientific answer if true, but it also means no KMT2A-directed drug programme should count these patients in its addressable population.

1. Does the KMT2A CXXC insert change YAP1's genomic occupancy, or does the YKY protein sit where a plain YAP1 fusion sits? A YAP1 ChIP in a YKY-expressing line against a YAP1-overexpressing control would answer it and has never been run.
2. The sarcoma allele retains YAP1 S127, the LATS1/2 site that normally exports YAP1 to the cytoplasm. Is the YKY protein still Hippo-regulated, and if so what makes it oncogenic?
3. Is YAP1's C-terminal PDZ-binding motif required for transformation by this allele, as it is for CCN2/CTGF induction by other YAP1 constructs?
4. Is there any KMT2A fusion anywhere in the leukaemia literature whose partner is a transcription-factor co-activator rather than elongation machinery, and if not, is that a property of the biology or of the partner-capture assays used?

1. E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   Fetched from live UniProt (2026-09-21): P46937, primary gene name read back as YAP1, 504 aa, recommended name Transcriptional coactivator YAP1, with WW domains at aa 171-204 and 230-263 and a transactivation region annotated at aa 291-504.

   UniProtKB P46937 (YAP1_HUMAN), Transcriptional coactivator YAP1, feature table and sequence · UniProt Consortium · UniProtKB 2026
   ▸What this evidence cannot show

   P46937 is one of several YAP1 isoforms and the literature numbers YAP1 residues in at least two frames (a 488-aa YAP1-1 and a 504-aa YAP1-2 form), so a residue quoted from a paper must be checked against the isoform that paper used. UniProt does not annotate a discrete 'TEAD-binding domain' feature; that assignment comes from the structural and fusion literature, not from the feature table.

   ▸Evidence that argues against this (1)

   • Isoform ambiguity is a real hazard here rather than a formality: the C-terminal phosphodegron and the transactivation-domain boundaries shift between the 488-aa and 504-aa numbering, so a claim about which YAP1 regulatory elements the sarcoma allele loses cannot be made from residue numbers alone and is stated here in exon terms instead. Ensembl (EMBL-EBI) 2026
2. E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   Computed here from live Ensembl REST (2026-09-21): YAP1 canonical transcript ENST00000282441 has 9 CDS exons encoding 504 aa, with exon 1 = aa 1-107, exon 2 = 108-191, exon 3 = 191-230, exon 4 = 230-268, exons 5-8 = 268-426 and exon 9 = 426-504.

   Ensembl REST API lookup, YAP1 (ENSG00000137693), canonical transcript ENST00000282441 with exon and translation coordinates · Ensembl (EMBL-EBI) · Ensembl REST 2026
   ▸What this evidence cannot show

   Codon ranges computed by cumulative CDS length; boundary codons appear in both flanking exons. YAP1 exon numbering in the sarcoma papers is not explicitly tied to a transcript accession in every report, so the mapping of a reported 'YAP1 exon 5' to these coordinates is an inference from the fact that the field reports a 9-exon gene.

   ▸Evidence that argues against this (1)

   • Alternative splicing of the WW-domain region produces YAP1 isoforms with one or two WW domains, so an exon index alone does not fix which WW complement a given allele encodes. UniProt Consortium 2026
3. E3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In human epithelioid haemangioendothelioma, a novel YAP1-TFE3 fusion defines a distinct subset of the tumour, establishing YAP1 as a recurrent 5' fusion partner in a lineage unrelated to the KMT2A-rearranged sarcomas.

   Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. · Antonescu CR, Le Loarer F, Mosquera JM, et al. · Genes Chromosomes Cancer 2013
   PMID 23737213DOI
   ▸What this evidence cannot show

   Cited here only to establish that YAP1 recurs as a fusion 5' partner across tumour types; no claim is made that YAP1::TFE3 and YAP1::KMT2A share a mechanism. Abstract-level reading; the exon structure of YAP1::TFE3 was not compared with the sarcoma allele here.

   ▸Evidence that argues against this (1)

   • One reported YAP1::KMT2A sarcoma expressed ERG, CD31, CD34, D2-40 and TFE3 by immunohistochemistry and could not be distinguished from epithelioid haemangioendothelioma on morphology, so the separation between the YAP1::TFE3 and YAP1::KMT2A tumour families is not always clean at the bench. Fumagalli C et al. 2025
4. E4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In childhood supratentorial ependymoma, YAP1-MAMLD1 fusion defines an entity with characteristic clinical, radiological, cytogenetic and histopathological features - a second lineage in which a YAP1 fusion is the defining lesion.

   Childhood supratentorial ependymomas with YAP1-MAMLD1 fusion: an entity with characteristic clinical, radiological, cytogenetic and histopathological features. · Andreiuolo F, Varlet P, Tauziède-Espariat A, et al. · Brain Pathol 2019
   PMID 30246434DOI
   ▸What this evidence cannot show

   Paediatric CNS tumours, not soft tissue, and cited only for the cross-lineage recurrence of YAP1 as a fusion partner. Abstract-level reading; no comparison of YAP1 breakpoints with the sarcoma allele was performed.

   ▸Evidence that argues against this (1)

   • A cross-lineage YAP1-fusion family is an argument that YAP1 is the driver in all of them, but it is equally consistent with YAP1 being a promiscuous, highly recombinogenic locus. Neither reading is settled, and no study has compared the YAP1 contribution across the three fusion families side by side. Antonescu CR et al. 2013
5. E5strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In a screen of 14,680 human sarcomas, YAP1 was the predominant KMT2A rearrangement partner (16 of 34 KMT2A-fusion-positive cases, 47%), with KMT2A supplying only its CxxC-domain exons while YAP1 supplied the TEAD-binding N-terminus and the C-terminal PDZ-binding motif.

   Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions. · Massoth LR, Hung YP, Nardi V, et al. · Mod Pathol 2020
   PMID 32461620DOI
   ▸What this evidence cannot show

   A commercial comprehensive-genomic-profiling cohort enriched for advanced, aggressive disease; the 47% is the share of KMT2A-rearranged sarcomas, not of sarcomas. The assignment of retained YAP1 elements is the authors' domain reasoning from exon indices, not a protein measurement.

   ▸Evidence that argues against this (1)

   • In the same cohort, 16 of the 34 KMT2A-rearranged sarcomas had unique non-recurrent partners, diverse histologies, a median age of 57 and TP53 mutation in 44%, and the authors call them 'of unclear significance'. So KMT2A rearrangement in a sarcoma is not always an entity-defining event, and YAP1's 47% is a share of a heterogeneous denominator. Warmke LM et al. 2025
6. E6moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper

   In mouse and human hepatocellular carcinoma, wild-type menin promotes carcinogenesis and epigenetically up-regulates Yap1 transcription - a menin-upstream-of-YAP1 relationship with no fusion protein involved.

   Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription. · Xu B, Li SH, Zheng R, et al. · Proc Natl Acad Sci U S A 2013
   PMID 24101467DOI
   ▸What this evidence cannot show

   Liver, not sarcoma; wild-type menin, not a KMT2A fusion; and abstract-level reading. Recorded here specifically to prevent it being mistaken later for evidence of a menin-YAP1 axis in KMT2A-rearranged sarcoma. It is the only record returned by menin[tiab] AND YAP1[tiab] (1 record, PubMed esearch, 2026-09-21, querytranslation "menin"[Title/Abstract] AND "YAP1"[Title/Abstract]).

   ▸Evidence that argues against this (1)

   • The direction of this relationship is the reverse of anything the sarcoma allele could do: it places menin upstream of YAP1 expression, whereas in the sarcoma YAP1 is the fusion scaffold and menin has no binding site on the fusion at all. Read as support for a menin-YAP1 mechanism in sarcoma it would be an error, and no study connects the two. Massoth LR et al. 2020
7. E_q95_yap1_loc1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database

   YAP1 has the best-annotated localisation record in this tranche by an order of magnitude and its compartment is a REGULATED TWO-STATE VARIABLE: UniProt P46937 carries Cytoplasm on TWELVE ECO:0000269 citations and Nucleus on SEVENTEEN, plus Cell membrane and a by-similarity tight-junction call, and the note specifies the switches - phosphorylation sequesters YAP1 in the cytoplasm by inhibiting its nuclear translocation; at LOW CELL DENSITY it is predominantly nuclear and is translocated to the cytoplasm at HIGH density; PTPN14 induces nucleus-to-cytoplasm translocation; in the nucleus, phosphorylation by PRP4K induces NUCLEAR EXCLUSION; AMOT isoform 1 and AMOTL2 localise it to the cytoplasm and tight junctions; and it is found at the cell membrane in keratinocytes in response to MECHANICAL STRAIN.

   UniProtKB P46937 (YAP1_HUMAN), SUBCELLULAR LOCATION comment for the cytoplasmic, nuclear, membrane and junctional pools with evidence codes and sources, fetched live 2026-09-22 · UniProt Consortium · Databases 2026
   ▸What this evidence cannot show

   Twenty-nine experimental citations make this a well-supported record rather than a well-audited one - this beat did not open all twenty-nine, so no rule-91 verdict is offered on the record as a whole, only the observation that the annotation is dense and internally consistent with a regulated shuttle. Every citation is from non-haematopoietic, non-sarcoma systems.

   ▸Evidence that argues against this (1)

   • THE DENSITY OF THIS RECORD IS ITSELF A FINDING ABOUT THE OTHER FIFTEEN GENES, AND IT ARGUES AGAINST A CONCLUSION A READER MIGHT DRAW FROM THIS TRANCHE. Thirteen of the sixteen entries audited here have compartment annotations resting on curator inference, family rules, cross-species propagation or papers about other proteins - and it would be easy to conclude that UniProt's localisation layer is generally unreliable. YAP1 refutes that: when a compartment has been the subject of a field's attention, the record has twenty-nine experimental citations and a note that reads like a review. The variable is not the database, it is whether anybody studied the question. That reframes the tranche's result: the weakness this beat found is a weakness in the LITERATURE for proteins nobody localised, faithfully reflected by the database, plus a smaller set of genuine curation errors where a citation points at the wrong compartment. Hao Y et al. 2008
8. E_q95_yap1_loc2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.paper

   The two switches that set YAP1's compartment are mechanistically separate and are mapped to different residues: LATS1 is a negative regulator of YAP whose phosphorylation drives cytoplasmic sequestration, and a coordinated phosphorylation by Lats and CK1 additionally regulates YAP STABILITY through SCF(beta-TRCP) - so one set of sites controls WHERE the protein is and another controls HOW LONG IT LASTS. UniProt's feature table places LATS1/LATS2 phosphoserines at residues 61, 109, 127, 164 and 397, and CK1 phosphoserines at 400 and 403, in the 504-residue canonical isoform P46937-1.

   A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP). · Zhao B, Li L, Tumaneng K, Wang CY, Guan KL · Genes Dev 2010
   PMID 20048001DOI
   ▸What this evidence cannot show

   RESIDUE NUMBERING IS A TRAP HERE and this entry states the frame explicitly: the site the Hippo literature usually calls S381 is numbered differently in the 504-residue canonical isoform that UniProt displays and that this graph uses, so a number copied from a paper cannot be compared with a number copied from the feature table without checking which isoform each used. UniProt annotates nine isoforms for YAP1. All residue positions asserted here are read from the canonical P46937-1 feature table fetched 2026-09-22, and no cross-isoform mapping is claimed.

   ▸Evidence that argues against this (1)

   • AND THE SEPARATION OF THE TWO SWITCHES IS WHAT MAKES THE FUSION INTERESTING, WHICH IS AN ARGUMENT THAT THE COMPARTMENT QUESTION FOR YKY IS NOT THE SAME AS THE COMPARTMENT QUESTION FOR YAP1. In the commonest architecture of this rearrangement - 13 of 15 fully evaluated cases - YAP1 exons 1-5 and exon 9 are retained and exons 6-8 are replaced by the KMT2A insert. On this graph's own exon map (exon 2 = aa 108-191, exon 8 = aa 388-426) that retains residue 127, the LATS1/2 site in the cytoplasmic-sequestration switch, and DELETES residues 397, 400 and 403, the LATS-plus-CK1 cluster in the stability switch. So the chimera is predicted to keep the signal that holds YAP1 out of the nucleus and lose the signal that destroys it, while simultaneously carrying KMT2A's CxxC zinc finger, whose job is to bind unmethylated CpG island DNA. A protein cannot be cytoplasmically sequestered and reading CpG islands at the same time, and nobody has looked at where this fusion protein is. Massoth LR et al. 2020
9. E_q95_yap1_loc3strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper

   In the two published YAP1::KMT2A sarcoma case reports that performed immunohistochemistry, NOBODY STAINED FOR YAP1. One case, a 31-year-old man with a suboccipital tumour and a YAP1 exon5::KMT2A exon4 fusion by next-generation sequencing, was stained for cyclin D1 (diffusely positive), MUC4, desmin, myogenin, beta-catenin, STAT6, myoD1, SMA and S100P. The other, a 65-year-old woman with a leg tumour, was stained for ERG, CD31, CD34, D2-40 and TFE3 (all positive) and MUC4, CAMTA1, SMA, desmin, S100 and keratins (negative), and required RNA-seq clustering against a sarcoma reference to be classified at all. Neither panel includes an antibody against the fusion's own 5-prime partner.

   YAP1::KMT2A fusion-positive sarcoma: An emerging soft tissue tumor entity with morphological features resembling a sclerosing epithelioid fibrosarcoma. · Agarwal A, Rekhi B, Goel V, Bajpai J, Rastogi S · Indian J Pathol Microbiol 2024
   PMID 38975722DOI
   ▸What this evidence cannot show

   Two case reports, n = 1 each, and immunohistochemistry panels are chosen for differential diagnosis rather than for mechanism - a pathologist has no reason to stain for YAP1 when the fusion is already proven by sequencing. This is therefore a statement about what the published record contains, not a criticism of either study. It is nonetheless the closest the literature comes to looking at where this fusion protein sits in a patient's tumour, and the answer is that the reagent was in the building and was never used.

   ▸Evidence that argues against this (1)

   • ONE OF THOSE PANELS CONTAINS A RESULT THAT IS AN INDIRECT LOCALISATION ARGUMENT AND IT POINTS THE OTHER WAY, WHICH IS WORTH MORE THAN THE MISSING STAIN. The first case is DIFFUSELY POSITIVE FOR CYCLIN D1. CCND1 is a canonical YAP/TEAD target gene, and YAP1 activates transcription only from the NUCLEUS - so a tumour with strong cyclin D1 expression and a YAP1-containing fusion is indirect evidence that the chimera is transcriptionally active and therefore nuclear, despite retaining residue 127. That is a testable prediction rather than a conclusion: cyclin D1 has many drivers, the case reports do not test TEAD dependence, and CDK4 - cyclin D1's partner kinase and another entry in this tranche - is separately reported to require its D-cyclin to enter the nucleus at all. A YAP1 stain plus a TEAD-target panel on archival material would settle it, and it needs no new tissue. Fumagalli C et al. 2025
10. E_q95_yap1_loc4strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.database

    Bounded 2026-09-22: YAP1 has NO subnuclear compartment in the literature, and the query that appears to find one is 56% nomenclature noise. YAP1[tiab] returns 3,934 records; with a localisation clause 1,002 - the largest localisation literature in this tranche; with the twelve-term subnuclear clause 16, of which NINE are SNHG1, SNHG3, SNHG6, SNHG12, SNHG16 and related long-noncoding-RNA papers matching through 'small NUCLEOLAR RNA host gene', and the remainder are lamin A/C mechanotransduction papers, a nuclear-speckle-rehabilitation study and a TAZ phase-separation paper about the PARALOGUE. Against the nine-term KMT2A/MLL fusion clause the gene clause returns 20, with a localisation clause 2 - both YAP1::KMT2A sarcoma case reports - and with a subnuclear clause 0.

    NCBI E-utilities esearch db=pubmed; every count stored with the querytranslation read back, in data.localization_bounded_absence · NCBI E-utilities · Databases 2026
    ▸What this evidence cannot show

    Titles and abstracts only; supporting figures not searched (rule 80). The registry's YAP1/YAP row was read before the first query and obeyed: every count here is on YAP1, never bare YAP, because YAP[tiab] returns 10,410 records against YAP1's 3,904 and yet recovers only 4 of the 17 in the KMT2A intersection.

    ▸Evidence that argues against this (1)

    • A NEW TOKEN HAZARD WAS MEASURED HERE AND IT IS NOT IN THE REGISTRY: 'condensate*' IS CONTAMINATED BY SMOKE CONDENSATE. YAP1[tiab] AND (condensate*[tiab] OR 'phase separation'[tiab]) returns 15 records whose title-checked first ten include cigarette smoke condensate, waterpipe smoke condensate and an amiodarone-toxicity yeast study. The direction is false-POSITIVE, which is the dangerous one, and it reaches further than this gene: this project holds condensate claims on the SEC, PRC1/CBX2, NUP98-FG and the ENL hotspot, and any bounded count built on the wildcard is inflated by a toxicology literature with no relation to phase separation. This is the second contaminated compartment token measured in this tranche, alongside a fourth independent confirmation of the registry's 'nucleolar' row - 9 of 16 here, 2 of 2 on USP8, roughly 19 of 20 on CDK4, 3 of 6 on SREBF1. Ni W et al. 2024

• ← fuses withYAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away

  KMT2A CXXC exons inserted between YAP1 exons 4/5 and 8/9, replacing YAP1 exons 5/6-8

• part of →YAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away

  supplies the TEAD-binding N-terminus and the PDZ-binding C-terminus of the YKY allele

• fuses with →KMT2A / MLL1 — the gene that breaks

  predominant KMT2A rearrangement partner in soft tissue sarcoma (16 of 34)

• related to →MEN1 / menin — the adaptor the fusion cannot work without

  wild-type menin up-regulates Yap1 transcription in hepatocellular carcinoma - a different tissue, different direction, no fusion

• ← related toEvery published KMT2A partner in sarcoma, counted - plus the papers this beat read and did not use, so the next beat does not repeat the search without the decisions

  dominant partner, 16 of 34

• related to →YAP1::KMT2A::YAP1 (YKY) - an insertional KMT2A rearrangement that keeps the CXXC zinc finger and throws the menin-binding exon away

  A TESTABLE CONTRADICTION IN THE CHIMERA'S ADDRESS. Variant I retains YAP1 exons 1-5 and exon 9: residue 127, the LATS1/2 cytoplasmic-sequestration site, is RETAINED (exon 2 = aa 108-191) while residues 397, 400 and 403 - the LATS-plus-CK1 stability cluster acting through SCF(beta-TRCP) - are DELETED with exon 8 (aa 388-426). So the fusion keeps the signal that holds YAP1 out of the nucleus, loses the signal that destroys it, and carries KMT2A's CpG-binding CxxC. Nobody has imaged it (Q95 2026-09-22)

• related to →KMT2A-rearranged soft tissue sarcoma - the same gene as infant B-ALL, in a young adult's leg, as a solid tumour

  In the two published YAP1::KMT2A cases with immunohistochemistry, NOBODY STAINED FOR YAP1 - the panels cover cyclin D1, MUC4, ERG, CD31, CD34, D2-40, TFE3, CAMTA1, desmin, myogenin, beta-catenin, STAT6, myoD1, SMA, S100 and keratins (PMIDs 38975722, 40879254). Indirect evidence points nuclear: one case is diffusely CYCLIN D1 positive and CCND1 is a YAP/TEAD target. A YAP1 stain plus a TEAD-target panel on archival material would settle it (Q95 2026-09-22)

• related to →A partner's 'normal' compartment is usually read off a different tissue, and for at least two KMT2A partners that reading is wrong in blood cells

  YAP1 is this node's counter-example and it reframes the tranche: 29 experimental ECO:0000269 citations and a note that reads like a review, because the field studied the question. Thirteen of sixteen genes audited here have compartment annotations resting on curator inference, family rules, cross-species loops or papers about other proteins - the variable is not the database, it is whether anybody looked (Q95 2026-09-22)

• ← co-occurs withAHDC1 (Gibbin) - an AT-hook chromatin-architecture factor that is already a cofactor of a DIFFERENT sarcoma fusion oncoprotein, and whose KMT2A breakpoint lands in an untranslated exon

  both partners of KMT2A in sarcoma whose own normal biology is a transcriptional regulator in mesenchyme - AHDC1 at enhancers, YAP1 as the coactivator of the recurrent arm