Yorkie homolog; 65 kD Yes-associated protein; YAP65 (YAP1, YAP65)

Function

• transcriptional regulator which can act both as a coactivator & a corepressor
• critical downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control & tumor suppression by restricting proliferation & promoting apoptosis
• the core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates & activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates & inactivates YAP1 oncoprotein
• YAP1 plays a key role to control cell proliferation in response to cell contact
• phosphorylation by LATS1/2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, & cell migration
• isoform 2 & isoform 3 can activate the C-terminal fragment (CTF) of ERBB4 (isoform 3)
• phosphorylated by LATS1 & LATS2
• phosphorylation inhibits its nuclear localization & activity & enhances interaction with YWHAB
• phosphorylated by protein kinase B
• binds to the SH3 domain of the YES kinase
• binds to WBP1 & WBP2
• binds, in vitro, through the WW1 domain, to neural isoforms of ENAH that contain the PPSY motif (putative)
• the phosphorylated form interacts with YWHAB
• interacts (via WW domains) with LATS1 (via PPxY motif 2)
• interacts with LATS2 isoform 2 & isoform 3 interact (via WW domain 1) with isoform 3 of ERBB4 (via PPxY motif 2)

Structure

• belongs to the YORKIE family
• contains 2 WW domains

Compartment

• cytoplasm, nucleus
• both phosphorylation & cell density can regulate its subcellular localization
• phosphorylation sequesters it in the cytoplasm by inhibiting its translocation into the nucleus
• at low density, predominantly nuclear
• translocated to the cytoplasm at high density

Alternative splicing

• named isoforms=3
• additional isoforms lacking the transactivation domain exist

Expression

• increased expression seen in some liver & prostate cancers
• isoforms lacking the transactivation domain found in striatal neurons of patients with Huntington disease (at protein level)

More general terms

• transcriptional adaptor protein; transcriptional coactivator
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=10413
• OMIM: https://mirror.omim.org/entry/606608
• UniProt: http://www.uniprot.org/uniprot/P46937.html