Search results for AURKA

Showing 28 results out of 37

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Protein (7 results from a total of 8)

Identifier: R-HSA-174254
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: O14965
Identifier: R-HSA-4655443
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: O14965
Identifier: R-HSA-2574832
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: AURKA: O14965
Identifier: R-HSA-6805089
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: AURKA: O14965
Identifier: R-HSA-4655367
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: AURKA: O14965
Identifier: R-HSA-8854040
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: O14965
Identifier: R-HSA-4655413
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: P63165

Reaction (7 results from a total of 14)

Identifier: R-HSA-8853419
Species: Homo sapiens
Compartment: cytosol
TPX2 promotes aurora kinase A (AURKA) activation via autophosphorylation of AURKA on threonine residue T288. Continuous association of TPX2 with AURKA facilitates active state conformation of AURKA and may prevent inactivation of AURKA by protein phosphatases (Bayliss et al. 2003).

Molecular dynamic simulations suggest the existence of two TPX2-dependent switches for Aurora A activation. 1) TPX2 binding to Aurora A forces lysine residue K143 of AURKA into an “open” state, which pulls ADP out of the ATP binding site in AURKA to promote kinase activation. 2) Arginine residue R180 of AURKA undergoes a “closed” movement upon TPX2 binding, thus capturing phosphorylated threonine T288 of AURKA into a buried position and locking AURKA in its active conformation. The existence of two TPX2-dependent switches in AURKA activation was further verified by the analysis of two AURKA mutants (K143A and R180A) (Xu et al. 2011).AURKA activation is enabled through phosphorylation and TPX2 binding; these two activating switches act synergistically and withough a predefined order (Dodson and Bayliss 2012).

Identifier: R-HSA-8853429
Species: Homo sapiens
Compartment: cytosol
Aurora kinase A binds PHLDA1 (TDAG51) and the two proteins co-localize in the cytosol (Johnson et al. 2011). Although phosphorylation of AURKA at threonine residue T288 within the catalytic loop of AURKA is needed for AURKA kinase activity (Walter et al. 2000), AURKA phosphorylation has not been specifically examined in the context of AURKA interaction with PHLDA1 and AURKA is therefore shown as unphosphorylated.
Identifier: R-HSA-4655404
Species: Homo sapiens
Compartment: cytosol, nucleoplasm
As inferred from mouse homologs, AURKA (Aurora-A) is SUMOylated at lysine-258 with SUMO1. AURKA, SUMO1, and UBE2I (UBC9) colocalize to centrisomes and the mitotic spindle. SUMOylation of AURKA is required for proper localization to the microtubules of the mitotic spindle therefore SUMOylated AURKA is assumed to be located on spindles in the cytosol during metphase.
Identifier: R-HSA-6791235
Species: Homo sapiens
Compartment: nucleoplasm
GADD45A binds Aurora-A protein kinase (AURKA). GADD45A inhibits the kinase activity of AURKA and AURKA-induced centrosome amplification, thus interfering with the G2/M transition (Shao et al. 2006, Sanchez et al. 2010).
Identifier: R-HSA-3000319
Species: Homo sapiens
Compartment: cytosol
BORA is able to interact with both AURKA (Aurora A kinase) and PLK1. Binding of BORA to PLK1 increases the accessibility of PLK1 threonine residue T210 and also brings PLK1 in proximity to AURKA, enabling AURKA to phosphorylate T210 of PLK1 and thereby activate PLK1 (Seki et al. 2008). While BORA is required for mitotic activation of AURKA in Drosophila (Hutterer et al. 2006), it does not significantly activate AURKA in human cells (Seki et al. 2008). AURKA is able to phosphorylate BORA in vitro, but the functional significance of this modification has not been determined (Hutterer et al. 2006).
Identifier: R-HSA-8853405
Species: Homo sapiens
Compartment: cytosol
TPX2 binds to aurora kinase A (AURKA) at centrosomes. The first 43 amino acids at the N-terminus of TPX2 are needed for binding to AURKA (Bayliss et al. 2003). HMMR (RHAMM) binds to TPX2 (Groen et al. 2004, Maxwell et al. 2005) and is involved in the proper localization of TPX2 to centrosomes and TPX2-mediated AURKA activation (Chen et al. 2014, Scrofani et al. 2015).

TPX2 binding to Aurora A protects premature AURKA degradation by APC/C-mediated proteolysis during early mitosis. TPX2 differentially regulates AURKA stability, activity and localization. While amino acids 1-43 in TPX2 facilitate complex formation between AURKA and TPX2 and promote kinase activation, they are insufficient for AURKA targeting to the mitotic spindle (Giubettini et al. 2011).

Identifier: R-HSA-6805103
Species: Homo sapiens
Compartment: nucleoplasm
AURKA (Aurora kinase A) phosphorylates TP53 (p53) on serine residue S315. This leads to destabilization of TP53 by enhancing MDM2 binding (Katayama et al. 2004). Based on Xenopus studies, AURKA-mediated phosphorylation of TP53 occurs in the presence of AURKA activator TPX2 (Pascreau et al. 2009).

Pathway (7 results from a total of 7)

Identifier: R-HSA-8854521
Species: Homo sapiens
PHLDA1 (TDAG51), the product of a gene involved in breast cancer progression, interacts with aurora kinase A (AURKA). While unphosphorylated PHLDA1 promotes AURKA ubiquitination and degradation, AURKA-mediated phosphorylation of PHLDA1 results in down-regulation of PHLDA1 protein levels. Ectopic expression of PHLDA1 strongly antagonizes AURKA-triggered oncogenic phenotypes, suggesting PHLDA1 downregulation as one of the key mechanisms by which AURKA promotes breast cancer (Johnson et al. 2011).
Identifier: R-HSA-8854518
Species: Homo sapiens
TPX2 binds to aurora kinase A (AURKA) at centrosomes and promotes its activation by facilitating AURKA active conformation and autophosphorylation of the AURKA threonine residue T288 (Bayliss et al. 2003, Xu et al. 2011, Giubettini et al. 2011, Dodson and Bayliss 2012).
Identifier: R-HSA-8854050
Species: Homo sapiens
Compartment: cytosol
The protein levels of aurora kinase A (AURKA) during mitotic entry and in early mitosis can be reduced by the action of the SCF-FBXL7 E3 ubiquitin ligase complex consisting of SKP1, CUL1, RBX1 and FBXL7 subunits. FBXL7 is the substrate recognition subunit of the SCF-FBXL7 complex that associates with the centrosome-bound AURKA, promoting its ubiquitination and proteasome-mediated degradation. Overexpression of FBXL7 results in G2/M cell cycle arrest and apoptosis (Coon et al. 2011).

FBXL7 protein levels are down-regulated by the action of the SCF-FBXL18 E3 ubiquitin ligase complex, consisting of SKP1, CUL1, RBX1 and the substrate recognition subunit FBXL18. FBXL18 binds to the FQ motif of FBXL7, targeting it for ubiquitination and proteasome-mediated degradation, counteracting its pro-apoptotic activity (Liu et al. 2015). Cell cycle stage-dependency of down-regulation of FBXL7 by FBXL18 is unknown.

Identifier: R-HSA-6804114
Species: Homo sapiens
TP53 contributes to the establishment of G2 arrest by inducing transcription of GADD45A and SFN, and by inhibiting transcription of CDC25C. TP53 induces GADD45A transcription in cooperation with chromatin modifying enzymes EP300, PRMT1 and CARM1 (An et al. 2004). GADD45A binds Aurora kinase A (AURKA), inhibiting its catalytic activity and preventing AURKA-mediated G2/M transition (Shao et al. 2006, Sanchez et al. 2010). GADD45A also forms a complex with PCNA. PCNA is involved in both normal and repair DNA synthesis. The effect of GADD45 interaction with PCNA, if any, on S phase progression, G2 arrest and DNA repair is not known (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010, Kim et al. 2013). SFN (14-3-3-sigma) is induced by TP53 (Hermeking et al. 1997) and contributes to G2 arrest by binding to the complex of CDK1 and CCNB1 (cyclin B1) and preventing its translocation to the nucleus. Phosphorylation of a number of nuclear proteins by the complex of CDK1 and CCNB1 is needed for G2/M transition (Chan et al. 1999). While promoting G2 arrest, SFN can simultaneously inhibit apoptosis by binding to BAX and preventing its translocation to mitochondria, a step involved in cytochrome C release (Samuel et al. 2001). TP53 binds the promoter of the CDC25C gene in cooperation with the transcriptional repressor E2F4 and represses CDC25C transcription, thus maintaining G2 arrest (St Clair et al. 2004, Benson et al. 2014). The zinc finger transcription factor ZNF385A (HZF) is a direct transcriptional target of TP53 that can form a complex with TP53 and facilitate TP53-mediated induction of SFN transcription (Das et al. 2007).
Identifier: R-HSA-2565942
Species: Homo sapiens
Compartment: cytosol
The kinase activity of PLK1 is required for cell cycle progression as PLK1 phosphorylates and regulates a number of cellular proteins during mitosis. Centrosomic AURKA (Aurora A kinase), catalytically activated through AJUBA facilitated autophosphorylation on threonine residue T288 at G2/M transition (Hirota et al. 2003), activates PLK1 on centrosomes by phosphorylating threonine residue T210 of PLK1, critical for PLK1 activity (Jang et al. 2002), in the presence of BORA (Macurek et al. 2008, Seki et al. 2008). Once activated, PLK1 phosphorylates BORA and targets it for ubiquitination mediated degradation by SCF-beta-TrCP ubiquitin ligases. Degradation of BORA is thought to allow PLK1 to interact with other substrates (Seki, Coppinger, Du et al. 2008, Seki et al. 2008).

The interaction of PLK1 with OPTN (optineurin) provides a negative-feedback mechanism for regulation of PLK1 activity. Phosphorylated PLK1 binds and phosphorylates OPTN associated with the Golgi membrane GTPase RAB8, promoting dissociation of OPTN from Golgi and translocation of OPTN to the nucleus. Phosphorylated OPTN facilitates the mitotic phosphorylation of the myosin phosphatase subunit PPP1R12A (MYPT1) and myosin phosphatase activation (Kachaner et al. 2012). The myosin phosphatase complex dephosphorylates threonine residue T210 of PLK1 and inactivates PLK1 (Yamashiro et al. 2008).
Identifier: R-HSA-6791312
Species: Homo sapiens
Under a variety of stress conditions, TP53 (p53), stabilized by stress-induced phosphorylation at least on S15 and S20 serine residues, can induce the transcription of genes involved in cell cycle arrest. Cell cycle arrest provides cells an opportunity to repair the damage before division, thus preventing the transmission of genetic errors to daughter cells. In addition, it allows cells to attempt a recovery from the damage and survive, preventing premature cell death.

TP53 controls transcription of genes involved in both G1 and G2 cell cycle arrest. The most prominent TP53 target involved in G1 arrest is the inhibitor of cyclin-dependent kinases CDKN1A (p21). CDKN1A is one of the earliest genes induced by TP53 (El-Deiry et al. 1993). CDKN1A binds and inactivates CDK2 in complex with cyclin A (CCNA) or E (CCNE), thus preventing G1/S transition (Harper et al. 1993). Nevertheless, under prolonged stress, the cell destiny may be diverted towards an apoptotic outcome. For instance, in case of an irreversible damage, TP53 can induce transcription of an RNA binding protein PCBP4, which can bind and destabilize CDKN1A mRNA, thus alleviating G1 arrest and directing the affected cell towards G2 arrest and, possibly, apoptosis (Zhu and Chen 2000, Scoumanne et al. 2011). Expression of E2F7 is directly induced by TP53. E2F7 contributes to G1 cell cycle arrest by repressing transcription of E2F1, a transcription factor that promotes expression of many genes needed for G1/S transition (Aksoy et al. 2012, Carvajal et al. 2012). ARID3A is a direct transcriptional target of TP53 (Ma et al. 2003) that may promote G1 arrest by cooperating with TP53 in induction of CDKN1A transcription (Lestari et al. 2012). However, ARID3A may also promote G1/S transition by stimulating transcriptional activity of E2F1 (Suzuki et al. 1998, Peeper et al. 2002).

TP53 contributes to the establishment of G2 arrest by inducing transcription of GADD45A and SFN, and by inhibiting transcription of CDC25C. TP53 induces GADD45A transcription in cooperation with chromatin modifying enzymes EP300, PRMT1 and CARM1 (An et al. 2004). GADD45A binds Aurora kinase A (AURKA), inhibiting its catalytic activity and preventing AURKA-mediated G2/M transition (Shao et al. 2006, Sanchez et al. 2010). GADD45A also forms a complex with PCNA. PCNA is involved in both normal and repair DNA synthesis. The effect of GADD45 interaction with PCNA, if any, on S phase progression, G2 arrest and DNA repair is not known (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010, Kim et al. 2013). SFN (14-3-3-sigma) is induced by TP53 (Hermeking et al. 1997) and contributes to G2 arrest by binding to the complex of CDK1 and CCNB1 (cyclin B1) and preventing its translocation to the nucleus. Phosphorylation of a number of nuclear proteins by the complex of CDK1 and CCNB1 is needed for G2/M transition (Chan et al. 1999). While promoting G2 arrest, SFN can simultaneously inhibit apoptosis by binding to BAX and preventing its translocation to mitochondria, a step involved in cytochrome C release (Samuel et al. 2001). TP53 binds the promoter of the CDC25C gene in cooperation with the transcriptional repressor E2F4 and represses CDC25C transcription, thus maintaining G2 arrest (St Clair et al. 2004, Benson et al. 2014).

Several direct transcriptional targets of TP53 are involved in cell cycle arrest but their mechanism of action is still unknown. BTG2 is induced by TP53, leading to cessation of cellular proliferation (Rouault et al. 1996, Duriez et al. 2002). BTG2 binds to the CCR4-NOT complex and promotes mRNA deadenylation activity of this complex. Interaction between BTG2 and CCR4-NOT is needed for the antiproliferative activity of BTG2, but the underlying mechanism has not been elucidated (Rouault et al. 1998, Mauxion et al. 2008, Horiuchi et al. 2009, Doidge et al. 2012, Ezzeddine et al. 2012). Two polo-like kinases, PLK2 and PLK3, are direct transcriptional targets of TP53. TP53-mediated induction of PLK2 may be important for prevention of mitotic catastrophe after spindle damage (Burns et al. 2003). PLK2 is involved in the regulation of centrosome duplication through phosphorylation of centrosome-related proteins CENPJ (Chang et al. 2010) and NPM1 (Krause and Hoffmann 2010). PLK2 is frequently transcriptionally silenced through promoter methylation in B-cell malignancies (Syed et al. 2006). Induction of PLK3 transcription by TP53 (Jen and Cheung 2005) may be important for coordination of M phase events through PLK3-mediated nuclear accumulation of CDC25C (Bahassi et al. 2004). RGCC is induced by TP53 and implicated in cell cycle regulation, possibly through its association with PLK1 (Saigusa et al. 2007). PLAGL1 (ZAC1) is a zinc finger protein directly transcriptionally induced by TP53 (Rozenfeld-Granot et al. 2002). PLAGL1 expression is frequently lost in cancer (Varrault et al. 1998) and PLAGL1 has been implicated in both cell cycle arrest and apoptosis (Spengler et al. 1997), but its mechanism of action remains unknown.

The zinc finger transcription factor ZNF385A (HZF) is a direct transcriptional target of TP53 that can form a complex with TP53 and facilitate TP53-mediated induction of CDKN1A and SFN (14-3-3 sigma) transcription (Das et al. 2007).

For a review of the role of TP53 in cell cycle arrest and cell cycle transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

Identifier: R-HSA-6804756
Species: Homo sapiens
Phosphorylation of TP53 (p53) at the N-terminal serine residues S15 and S20 plays a critical role in protein stabilization as phosphorylation at these sites interferes with binding of the ubiquitin ligase MDM2 to TP53. Several different kinases can phosphorylate TP53 at S15 and S20. In response to double strand DNA breaks, S15 is phosphorylated by ATM (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998), and S20 by CHEK2 (Chehab et al. 1999, Chehab et al. 2000, Hirao et al. 2000). DNA damage or other types of genotoxic stress, such as stalled replication forks, can trigger ATR-mediated phosphorylation of TP53 at S15 (Lakin et al. 1999, Tibbetts et al. 1999) and CHEK1-mediated phosphorylation of TP53 at S20 (Shieh et al. 2000). In response to various types of cell stress, NUAK1 (Hou et al. 2011), CDK5 (Zhang et al. 2002, Lee et al. 2007, Lee et al. 2008), AMPK (Jones et al. 2005) and TP53RK (Abe et al. 2001, Facchin et al. 2003) can phosphorylate TP53 at S15, while PLK3 (Xie, Wang et al. 2001, Xie, Wu et al. 2001) can phosphorylate TP53 at S20.

Phosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2 (Taira et al. 2007, Taira et al. 2010). TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1 (D'Orazi et al. 2002, Hofmann et al. 2002, Tomasini et al. 2003). CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death (Lee et al. 2007).

MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling (Sun et al. 2007).

NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes (Hou et al. 2011). S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).

The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) (Katayama et al. 2004) and CDK2 (Luciani et al. 2000). Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID (Li et al. 2004).

Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism (Wu et al. 2011). A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation (Gully et al. 2012).

Complex (7 results from a total of 8)

Identifier: R-HSA-4655329
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-8854031
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-3000302
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-8854038
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-8853432
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6805100
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-8853422
Species: Homo sapiens
Compartment: cytosol
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