Search results for WWTR1

Showing 19 results out of 40

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Protein (3 results from a total of 3)

Identifier: R-HSA-1629775
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: WWTR1: Q9GZV5
Identifier: R-HSA-1629773
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: WWTR1: Q9GZV5
Identifier: R-HSA-2028665
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: WWTR1: Q9GZV5

Reaction (6 results from a total of 22)

Identifier: R-HSA-2032768
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
In its unphosphorylated state, the WWTR1 (TAZ) transcriptional coactivator moves freely into the nucleus. Phosphorylated WWTR1 (TAZ), in contrast, is sequestered in the cytosol (Lei et al. 2008).
Identifier: R-HSA-2064932
Species: Homo sapiens
Compartment: nucleoplasm
In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind the RUNX2 transcription factor to form a complex. This interaction has not been experimentally characterized in human cells but is inferred from properties of the homologous mouse proteins. The stoichiometry of this complex is unknown (Cui et al. 2003).

Formation of the RUNX2:WWTR1 complex is implicated in promotion of luminal breast cancer progression through regulation of E-cadherin (CDH1) and cross-talk with ERBB2 (HER2) signaling (Brusgard et al. 2015).

Identifier: R-HSA-2032781
Species: Homo sapiens
Compartment: nucleoplasm
In the nucleus the WWTR1 (TAZ) transcriptional coactivator can bind any one of the four TEAD transcription factors to form a complex. The stoichiometry of this complex is unknown (Chan et al. 2009; Zhang et al. 2009).
Identifier: R-HSA-2060328
Species: Homo sapiens
Compartment: cytosol
Cytosolic phospho-LATS1, complexed with MOB1, catalyzes the phosphorylation of WWTR1 (TAZ) on serine residue 89. This activity of human LATS1 protein has not been demonstrated experimentally but is inferred from the activity of human paralogue LATS2 and of mouse homologue LATS1 (Varelas et al. 2010).
Identifier: R-HSA-2028661
Species: Homo sapiens
Compartment: cytosol
Cytosolic phospho-LATS2, complexed with MOB1, catalyzes the phosphorylation of WWTR1 (TAZ) on serine residue 89 (Lei et al. 2008). This reaction is positively regulated by the angiomotin proteins AMOT (130 kd form), AMOTL1, and AMOTL2, which may function by physically bridging LATS2 and YAP (Zhao et al. 2011).
Identifier: R-HSA-2031355
Species: Homo sapiens
Compartment: cytosol
In the cytosol of human embryonic stem cells, WWTR1 (TAZ) binds heterotrimer composed of two R-SMADs (SMAD2 and/or SMAD3) and SMAD4. This interaction involves the C-terminus of WWTR1 (TAZ) and the MH1 domain of SMAD proteins.

Pathway (3 results from a total of 3)

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-2173796
Species: Homo sapiens
After phosphorylated SMAD2 and/or SMAD3 form a heterotrimer with SMAD4, SMAD2/3:SMAD4 complex translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003). In the nucleus, linker regions of SMAD2 and SMAD3 within SMAD2/3:SMAD4 complex can be phosphorylated by CDK8 associated with cyclin C (CDK8:CCNC) or CDK9 associated with cyclin T (CDK9:CCNT). CDK8/CDK9-mediated phosphorylation of SMAD2/3 enhances transcriptional activity of SMAD2/3:SMAD4 complex, but also primes it for ubiquitination and consequent degradation (Alarcon et al. 2009).

The transfer of SMAD2/3:SMAD4 complex to the nucleus can be assisted by other proteins, such as WWTR1. In human embryonic cells, WWTR1 (TAZ) binds SMAD2/3:SMAD4 heterotrimer and mediates TGF-beta-dependent nuclear accumulation of SMAD2/3:SMAD4. The complex of WWTR1 and SMAD2/3:SMAD4 binds promoters of SMAD7 and SERPINE1 (PAI-1 i.e. plasminogen activator inhibitor 1) genes and stimulates their transcription (Varelas et al. 2008). Stimulation of SMAD7 transcription by SMAD2/3:SMAD4 represents a negative feedback loop in TGF-beta receptor signaling. SMAD7 can be downregulated by RNF111 ubiquitin ligase (Arkadia), which binds and ubiquitinates SMAD7, targeting it for degradation (Koinuma et al. 2003).

SMAD2/3:SMAD4 heterotrimer also binds the complex of RBL1 (p107), E2F4/5 and TFDP1/2 (DP1/2). The resulting complex binds MYC promoter and inhibits MYC transcription. Inhibition of MYC transcription contributes to anti-proliferative effect of TGF-beta (Chen et al. 2002). SMAD2/3:SMAD4 heterotrimer also associates with transcription factor SP1. SMAD2/3:SMAD4:SP1 complex stimulates transcription of a CDK inhibitor CDKN2B (p15-INK4B), also contributing to the anti-proliferative effect of TGF-beta (Feng et al. 2000).

MEN1 (menin), a transcription factor tumor suppressor mutated in a familial cancer syndrome multiple endocrine neoplasia type 1, forms a complex with SMAD2/3:SMAD4 heterotrimer, but transcriptional targets of SMAD2/3:SMAD4:MEN1 have not been elucidated (Kaji et al. 2001, Sowa et al. 2004, Canaff et al. 2012).

JUNB is also an established transcriptional target of SMAD2/3:SMAD4 complex (Wong et al. 1999).

Complex (6 results from a total of 11)

Identifier: R-HSA-2064404
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-2064405
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-9618554
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-2066300
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-2028649
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-2106580
Species: Homo sapiens
Compartment: nucleoplasm

Set (1 results from a total of 1)

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