Search results for YAP1

Showing 23 results out of 66

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Protein (5 results from a total of 7)

Identifier: R-HSA-1253322
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: YAP1: P46937
Identifier: R-HSA-1253345
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: YAP1: P46937
Identifier: R-HSA-8937857
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: P46937
Identifier: R-HSA-8937843
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: P46937
Identifier: R-HSA-2028554
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: P46937

Reaction (5 results from a total of 32)

Identifier: R-HSA-8956659
Species: Homo sapiens
Compartment: nucleoplasm
In response to DNA damage, ABL1 phosphorylates YAP1 on tyrosine residue Y407 (corresponds to Y357 in the YAP1 splicing isoform 3, known as YAP1-1beta, which was used in the study by Levy, Adamovich et al. 2008).
Identifier: R-HSA-2028724
Species: Homo sapiens
Compartment: cytosol
AMOT (130 KDa isoform), AMOTL1, and AMOTL2 can each bind YAP1 and sequester it in the cytosol. This interaction is not dependent on YAP1 phosphorylation and may thus be a means of negatively regulating YAP activity in addition to the ones dependent on Hippo pathway-dependent phosphorylation. AMOT - YAP1 binding is dependent on sequence motifs in the amino terminal portions of the AMOT proteins (and that are absent from the AMOT 80 KDa isoform, which does not bind YAP1) (Wang et al. 2010; Chan et al. 2011).
Identifier: R-HSA-8956639
Species: Homo sapiens
Compartment: nucleoplasm
RUNX1, presumably in complex with CBFB, binds to YAP1 (Levy, Adamovich et al. 2008; Levy, Reuven and Shaul 2008). Phosphorylation of YAP1 by ABL1 in response to DNA damage prevents binding of YAP1 to RUNX1 (Levy, Adamovich et al. 2008).
Identifier: R-HSA-8956676
Species: Homo sapiens
Compartment: nucleoplasm
YAP1, phosphorylated on tyrosine residue Y407 (Y357 in the splicing isoform 3, known as YAP1-1beta) by the protein tyrosine kinase ABL1, activated in response to DNA damage, forms a complex with TP73. ABL1-phosphorylated YAP1 can no longer bind RUNX1 (Levy, Adamovich et al. 2008; Levy, Reuven and Shaul 2008). Binding of phosphorylated YAP1 to TP73 may target TP73 to promoters of pro-apoptotic target genes instead of cell cycle arrest genes (Levy, Adamovich et al. 2008).
Identifier: R-HSA-8951676
Species: Homo sapiens
Compartment: nucleoplasm
RUNX3 interacts with both YAP1 and TEAD proteins. The interaction with YAP1 involves the PY motif of RUNX3 and the WW domain of YAP1. The interaction with TEADs involves the Runt domain of RUNX3 and the DNA recognition helix of TEADs. RUNX3 was shown to directly interact with TEAD1 and TEAD4. Based on sequence similarity, it is highly probable that RUNX3 also interacts with TEAD2 and TEAD3. The interaction of RUNX3 with YAP1 and/or TEADs does not prevent formation of the YAP1:TEADs complex (Yagi et al. 1999, Qiao et al. 2015).

Set (2 results from a total of 2)

Identifier: R-HSA-2028622
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9618556
Species: Homo sapiens
Compartment: nucleoplasm

Complex (5 results from a total of 18)

Identifier: R-HSA-2064400
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-2064401
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-8869643
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-1253341
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-1253347
Species: Homo sapiens
Compartment: nucleoplasm

Pathway (5 results from a total of 6)

Identifier: R-HSA-8951671
Species: Homo sapiens
Association of RUNX3 with the TEADs:YAP1 complex inhibits loading of the TEADs:YAP1 to the CTGF promoter, thus negatively regulating transcription of the CTGF gene which encodes the Connective tissue growth factor (Yagi et al. 1999, Zhao et al. 2008, Qiao et al. 2016).
Identifier: R-HSA-2032785
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
YAP1 and WWTR1 (TAZ) are transcriptional co-activators, both homologues of the Drosophila Yorkie protein. They both interact with members of the TEAD family of transcription factors, and WWTR1 interacts as well with TBX5 and RUNX2, to promote gene expression. Their transcriptional targets include genes critical to regulation of cell proliferation and apoptosis. Their subcellular location is regulated by the Hippo signaling cascade: phosphorylation mediated by this cascade leads to the cytosolic sequestration of both proteins (Murakami et al. 2005; Oh and Irvine 2010).
Identifier: R-HSA-2028269
Species: Homo sapiens
Compartment: cytosol
Human Hippo signaling is a network of reactions that regulates cell proliferation and apoptosis, centered on a three-step kinase cascade. The cascade was discovered by analysis of Drosophila mutations that lead to tissue overgrowth, and human homologues of its components have since been identified and characterized at a molecular level. Data from studies of mice carrying knockout mutant alleles of the genes as well as from studies of somatic mutations in these genes in human tumors are consistent with the conclusion that in mammals, as in flies, the Hippo cascade is required for normal regulation of cell proliferation and defects in the pathway are associated with cell overgrowth and tumorigenesis (Oh and Irvine 2010; Pan 2010; Zhao et al. 2010). This group of reactions is also notable for its abundance of protein:protein interactions mediated by WW domains and PPxY sequence motifs (Sudol and Harvey 2010).

There are two human homologues of each of the three Drosophila kinases, whose functions are well conserved: expression of human proteins rescues fly mutants. The two members of each pair of human homologues have biochemically indistinguishable functions. Autophosphorylated STK3 (MST2) and STK4 (MST1) (homologues of Drosophila Hippo) catalyze the phosphorylation and activation of LATS1 and LATS2 (homologues of Drosophila Warts) and of the accessory proteins MOB1A and MOB1B (homologues of Drosophila Mats). LATS1 and LATS2 in turn catalyze the phosphorylation of the transcriptional co-activators YAP1 and WWTR1 (TAZ) (homologues of Drosophila Yorkie).

In their unphosphorylated states, YAP1 and WWTR1 freely enter the nucleus and function as transcriptional co-activators. In their phosphorylated states, however, YAP1 and WWTR1 are instead bound by 14-3-3 proteins, YWHAB and YWHAE respectively, and sequestered in the cytosol.

Several accessory proteins are required for the three-step kinase cascade to function. STK3 (MST2) and STK4 (MST1) each form a complex with SAV1 (homologue of Drosophila Salvador), and LATS1 and LATS2 form complexes with MOB1A and MOB1B (homologues of Drosophila Mats).

In Drosophila a complex of three proteins, Kibra, Expanded, and Merlin, can trigger the Hippo cascade. A human homologue of Kibra, WWC1, has been identified and indirect evidence suggests that it can regulate the human Hippo pathway (Xiao et al. 2011). A molecular mechanism for this interaction has not yet been worked out and the molecular steps that trigger the Hippo kinase cascade in humans are unknown.

Four additional processes related to human Hippo signaling, although incompletely characterized, have been described in sufficient detail to allow their annotation. All are of physiological interest as they are likely to be parts of mechanisms by which Hippo signaling is modulated or functionally linked to other signaling processes. First, the caspase 3 protease cleaves STK3 (MST2) and STK4 (MST1), releasing inhibitory carboxyterminal domains in each case, leading to increased kinase activity and YAP1 / TAZ phosphorylation (Lee et al. 2001). Second, cytosolic AMOT (angiomotin) proteins can bind YAP1 and WWTR1 (TAZ) in their unphosphorylated states, a process that may provide a Hippo-independent mechanism to down-regulate the activities of these proteins (Chan et al. 2011). Third, WWTR1 (TAZ) and YAP1 bind ZO-1 and 2 proteins (Remue et al. 2010; Oka et al. 2010). Fourth, phosphorylated WWTR1 (TAZ) binds and sequesters DVL2, providing a molecular link between Hippo and Wnt signaling (Varelas et al. 2010).

Identifier: R-HSA-1251985
Species: Homo sapiens
Besides signaling as a transmembrane receptor, ligand activated homodimers of ERBB4 JM-A isoforms (ERBB4 JM-A CYT1 and ERBB4 JM-A CYT2) undergo proteolytic cleavage by ADAM17 (TACE) in the juxtamembrane region, resulting in shedding of the extracellular domain and formation of an 80 kDa membrane bound ERBB4 fragment known as ERBB4 m80 (Rio et al. 2000, Cheng et al. 2003). ERBB4 m80 undergoes further proteolytic cleavage, mediated by the gamma-secretase complex, which releases the soluble 80 kDa ERBB4 intracellular domain, known as ERBB4 s80 or E4ICD, into the cytosol (Ni et al. 2001). ERBB4 s80 is able to translocate to the nucleus, promote nuclear translocation of various transcription factors, and act as a transcription co-factor. In neuronal precursors, ERBB4 s80 binds the complex of TAB and NCOR1, helps to move the complex into the nucleus, and is a co-factor of TAB:NCOR1-mediated inhibition of expression of astrocyte differentiation genes GFAP and S100B (Sardi et al. 2006). In mammary cells, ERBB4 s80 recruits STAT5A transcription factor in the cytosol, shuttles it to the nucleus, and acts as the STAT5A co-factor in binding to and promoting transcription from the beta-casein (CSN2) promoter, and may be involved in the regulation of other lactation-related genes (Williams et al. 2004, Muraoka-Cook et al. 2008). ERBB4 s80 was also shown to bind activated estrogen receptor in the nucleus and act as its transcriptional co-factor in promoting transcription of some estrogen-regulated genes, such as progesterone receptor gene NR3C3 and CXCL12 i.e. SDF1 (Zhu et al. 2006). ERBB4s80 may inhibit transcription of telomerase reverse transcriptase (TERT) by increasing methylation of the TERT gene promoter through an unknown mechanism (Ishibashi et al. 2012).

The C-tail of ERBB4 possesses several WW-domain binding motifs (three in CYT1 isoform and two in CYT2 isoform), which enable interaction of ERBB4 with WW-domain containing proteins. ERBB4 s80, through WW-domain binding motifs, interacts with YAP1 transcription factor, a known proto-oncogene, and may be a co-regulator of YAP1-mediated transcription (Komuro et al. 2003, Omerovic et al. 2004). The tumor suppressor WWOX, another WW-domain containing protein, competes with YAP1 in binding to ERBB4 s80 and prevents translocation of ERBB4 s80 to the nucleus (Aqeilan et al. 2005). ERBB4 s80 is also able to translocate to the mitochondrial matrix, presumably when its nuclear translocation is inhibited. Once in the mitochondrion, the BH3 domain of ERBB4, characteristic of BCL2 family members, may enable it to act as a pro-apoptotic factor (Naresh et al. 2006).
Identifier: R-HSA-8940973
Species: Homo sapiens
The complex of RUNX2 and CBFB regulates transcription of genes involved in differentiation of osteoblasts.
RUNX2 stimulates transcription of the BGLAP gene, encoding osteocalcin (Ducy and Karsenty 1995, Ducy et al. 1997). Binding of the RUNX2:CBFB complex to the BGLAP gene promoter is increased when RUNX2 is phosphorylated on serine residue S451 (Wee et al. 2002). Osteocalcin, a bone-derived hormone, is one of the most abundant non-collagenous proteins of the bone extracellular matrix (reviewed in Karsenty and Olson 2016). Association of the activated androgen receptor (AR) with RUNX2 prevents binding of RUNX2 to the BGLAP promoter (Baniwal et al. 2009). When YAP1, tyrosine phosphorylated by SRC and/or YES1, binds to RUNX2 at the BGLAP gene promoter, transcription of the BGLAP gene is inhibited (Zaidi et al. 2004). Signaling by SRC is known to inhibit osteoblast differentiation (Marzia et al. 2000).
Simultaneous binding of RUNX2 and SP7 (Osterix, also known as OSX) to adjacent RUNX2 and SP7 binding sites, respectively, in the UCMA promoter, synergistically activates UCMA transcription. UCMA stimulates osteoblast differentiation and formation of mineralized nodules (Lee et al. 2015).
The SCF(SKP2) E3 ubiquitin ligase complex inhibits differentiation of osteoblasts by polyubiquitinating RUNX2 and targeting it for proteasome-mediated degradation (Thacker et al. 2016). This process is inhibited by glucose uptake in osteoblasts (Wei et al. 2015).

Icon (1 results from a total of 1)

YAP

Species: Homo sapiens
Curator: Karen Rothfels
Designer: Cristoffer Sevilla
YAP icon
Transcriptional coactivator YAP1
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