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YAP1

Wednesday 9 May 2012

WKP

Definition: YAP1 (yes-associated protein 1), also known as YAP or YAP65, is a protein that acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing apoptotic genes.

YAP1 is inhibited in the Hippo signaling pathway which allows the cellular control of organ size and tumor suppression. YAP1 was first identified by virtue of its ability to associate with the SH3 domain of Yes and Src protein tyrosine kinases.

YAP1 is a potent oncogene, which is amplified in various human cancers.

Pathology

- YAP1 is a potent oncogene, which is amplified in various human cancers.

- TFE3-YAP1 fusion gene in a small subset (@<@5%) of epithelioid hemangioendothelioma (EHE)

  • Epithelioid hemangioendothelioma (EHE) is a malignant endothelial neoplasm characterized by recurrent translocations involving chromosomal regions 1p36.3 and 3q25, resulting in the formation of a WWTR1-CAMTA1 fusion gene in approximately 90% of cases.
  • A WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma of different anatomic sites. (21584898)

- YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. (19952108)

  • Medulloblastoma is the most common solid malignancy of childhood, with treatment side effects reducing survivors’ quality of life and lethality being associated with tumor recurrence.
  • Activation of the Sonic hedgehog (Shh) signaling pathway is implicated in human medulloblastomas.
  • Cerebellar granule neuron precursors (CGNPs) depend on signaling by the morphogen Shh for expansion during development, and have been suggested as a cell of origin for certain medulloblastomas.
  • Tere is an up-regulation of the oncogenic transcriptional coactivator yes-associated protein 1 (YAP1), which is negatively regulated by the Hippo pathway, in human medulloblastomas with aberrant Shh signaling.
  • Consistent with conserved mechanisms between brain tumorigenesis and development, Shh induces YAP1 expression in CGNPs.
  • Shh also promotes YAP1 nuclear localization in CGNPs, and YAP1 can drive CGNP proliferation.
  • YAP1 is found in cells of the perivascular niche, where proposed tumor-repopulating cells reside.
  • Post-irradiation, YAP1 was found in newly growing tumor cells.
  • YAP1 as a new Shh effector that may be targeted by medulloblastoma therapies aimed at eliminating medulloblastoma recurrence.

- Heterozygous loss-of-function mutations in the YAP1 gene have been identified in two families with major eye malformations with or without extra-ocular features such as hearing loss, cleft lip, intellectual disability and renal disease.

Targeted therapy

- The YAP1 oncogene serves as a target for the development of new cancer drugs. Small compounds have been identified that disrupt the YAP1-TEAD complex or block the binding function of WW domains. These small molecules represent lead compounds for the development of therapies for cancer patients, who harbor amplified or overexpressed YAP oncogene.

References

- YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Fernandez-L A, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, Taylor MD, Kenney AM. Genes Dev. 2009 Dec 1;23(23):2729-41. PMID: 19952108 [Free]

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