BioPAX pathway converted from "HSF1-dependent transactivation" in the Reactome database.

HSF1-dependent transactivation

Acquisition of DNA binding activity by HSF1 is necessary but insufficient for transcriptional activation (Cotto JJ et al. 1996; Trinklein ND et al. 2004). In addition to having a sequence-specific DNA binding domain, HSF1 contains a C-terminal region which is involved in activating the transcription of the target genes (Green M et al. 1995). However, the transactivating ability of the transactivation domain itself is not stress sensitive. Rather, it's controled by a regulatory domain of HSF1 (amino acids 221-310), which represses the transactivating ability under normal physiological conditions (Green M et al. 1995; Zuo J et al. 1995; Newton EM et al. 1996). The HSF1 transactivation domain can be divided into two distinct regions, activation domain 1 (AD1) and activation domain 2 (AD2) (Brown SA et al. 1998). AD1 and AD2 each contain residues that are important for both transcriptional initiation and elongation. Mutations in acidic residues in both AD1 and AD2 preferentially affect the ability of HSF1 to stimulate transcriptional initiation, while mutations in phenylalanine residues preferentially affect stimulation of elongation (Brown SA et al. 1998). Activation of the DNA-bound but transcriptionally incompetent HSF1 is thought to occur upon stress induced HSF1 phosphorylation at several serine residues (Ding XZ et al. 1997; Holmberg CI et al. 2001; Guettouche T et al. 2005). In cells exposed to heat, acquisition of HSE DNA-binding activity was observed to precede phosphorylation of HSF1 (Cotto JJ et al. 1996; Kline MP & Morimoto RI 1997). While there is a sufficient evidence to suggest that phosphorylation of HSF1 is essential to modulate HSF1 transactiviting capacity, mechanisms behind stress stimuli and kinases/phosphatases involved have not been clearly established.

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

2.7.11

Phosphorylation of HSF1 at Ser326 induces transactivation

Mutagenesis experiments and functional studies suggest that phosphorylation of HSF1 residue Ser326 promotes induction of the HSF1 transcriptional competence in response to heat and other cell stressors including proteasome inhibitors and sodium arsenite (Guettouche T et al. 2005; Chou SD et al. 2012).The mammalian target of rapamycin complex 1 (mTORC1) has been implicated in sensing intracellular protein misfolding (Qian SB et al. 2010; Chou SD et al. 2012). RNA interference?mediated repression of mTOR kinase activity in human HeLa cells was found to increase sensitivity to heat shock. Moreover, inhibition of HSF1 phosphorylation on Ser326 by rapamycin suggests that this site in HSF1 is a target for the mTORC1complex (Chou SD et al. 2012).

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 4793790

nucleoplasmGO0005654HSF1 trimer [nucleoplasm]

HSF1 trimer

Reactome DB_ID: 3371416

UniProt:Q00613 HSF1

HSF1

HSF1HSTF1FUNCTION Functions as a stress-inducible and DNA-binding transcription factor that plays a central role in the transcriptional activation of the heat shock response (HSR), leading to the expression of a large class of molecular chaperones heat shock proteins (HSPs) that protect cells from cellular insults' damage (PubMed:1871105, PubMed:11447121, PubMed:1986252, PubMed:7760831, PubMed:7623826, PubMed:8946918, PubMed:8940068, PubMed:9341107, PubMed:9121459, PubMed:9727490, PubMed:9499401, PubMed:9535852, PubMed:12659875, PubMed:12917326, PubMed:15016915, PubMed:25963659, PubMed:26754925). In unstressed cells, is present in a HSP90-containing multichaperone complex that maintains it in a non-DNA-binding inactivated monomeric form (PubMed:9727490, PubMed:11583998, PubMed:16278218). Upon exposure to heat and other stress stimuli, undergoes homotrimerization and activates HSP gene transcription through binding to site-specific heat shock elements (HSEs) present in the promoter regions of HSP genes (PubMed:1871105, PubMed:1986252, PubMed:8455624, PubMed:7935471, PubMed:7623826, PubMed:8940068, PubMed:9727490, PubMed:9499401, PubMed:10359787, PubMed:11583998, PubMed:12659875, PubMed:16278218, PubMed:25963659, PubMed:26754925). Activation is reversible, and during the attenuation and recovery phase period of the HSR, returns to its unactivated form (PubMed:11583998, PubMed:16278218). Binds to inverted 5'-NGAAN-3' pentamer DNA sequences (PubMed:1986252, PubMed:26727489). Binds to chromatin at heat shock gene promoters (PubMed:25963659). Plays also several other functions independently of its transcriptional activity. Involved in the repression of Ras-induced transcriptional activation of the c-fos gene in heat-stressed cells (PubMed:9341107). Positively regulates pre-mRNA 3'-end processing and polyadenylation of HSP70 mRNA upon heat-stressed cells in a symplekin (SYMPK)-dependent manner (PubMed:14707147). Plays a role in nuclear export of stress-induced HSP70 mRNA (PubMed:17897941). Plays a role in the regulation of mitotic progression (PubMed:18794143). Plays also a role as a negative regulator of non-homologous end joining (NHEJ) repair activity in a DNA damage-dependent manner (PubMed:26359349). Involved in stress-induced cancer cell proliferation in a IER5-dependent manner (PubMed:26754925).FUNCTION (Microbial infection) Plays a role in latent human immunodeficiency virus (HIV-1) transcriptional reactivation. Binds to the HIV-1 long terminal repeat promoter (LTR) to reactivate viral transcription by recruiting cellular transcriptional elongation factors, such as CDK9, CCNT1 and EP300.SUBUNIT Monomer; cytoplasmic latent and transcriptionally inactive monomeric form in unstressed cells (PubMed:8455624, PubMed:7935376, PubMed:7935471, PubMed:7623826, PubMed:9222587, PubMed:9727490, PubMed:11583998). Homotrimer; in response to stress, such as heat shock, homotrimerizes and translocates into the nucleus, binds to heat shock element (HSE) sequences in promoter of heat shock protein (HSP) genes and acquires transcriptional ability (PubMed:8455624, PubMed:7935471, PubMed:7623826, PubMed:9222587, PubMed:9727490, PubMed:11583998, PubMed:26754925, PubMed:26727489). Interacts (via monomeric form) with FKBP4; this interaction occurs in unstressed cells (PubMed:11583998). Associates (via monomeric form) with HSP90 proteins in a multichaperone complex in unnstressed cell; this association maintains HSF1 in a non-DNA-binding and transcriptional inactive form by preventing HSF1 homotrimerization (PubMed:9727490, PubMed:11583998, PubMed:15661742, PubMed:16278218). Homotrimeric transactivation activity is modulated by protein-protein interactions and post-translational modifications (PubMed:11583998, PubMed:15016915, PubMed:16554823, PubMed:26754925). Interacts with HSP90AA1; this interaction is decreased in a IER5-dependent manner, promoting HSF1 accumulation in the nucleus, homotrimerization and DNA-binding activities (PubMed:26754925). Part (via regulatory domain in the homotrimeric form) of a large heat shock-induced HSP90-dependent multichaperone complex at least composed of FKBP4, FKBP5, HSP90 proteins, PPID, PPP5C and PTGES3; this association maintains the HSF1 homotrimeric DNA-bound form in a transcriptionally inactive form (PubMed:9727490, PubMed:11583998, PubMed:16278218). Interacts with BAG3 (via BAG domain); this interaction occurs in normal and heat-shocked cells promoting nuclear shuttling of HSF1 in a BAG3-dependent manner (PubMed:26159920). Interacts (via homotrimeric and hyperphosphorylated form) with FKBP4; this interaction occurs upon heat shock in a HSP90-dependent multichaperone complex (PubMed:11583998). Interacts (via homotrimeric form preferentially) with EEF1A proteins (PubMed:15016915). In heat shocked cells, stress-denatured proteins compete with HSF1 homotrimeric DNA-bound form for association of the HSP90-dependent multichaperone complex, and hence alleviating repression of HSF1-mediated transcriptional activity (PubMed:11583998). Interacts (via homotrimeric form preferentially) with DAXX; this interaction relieves homotrimeric HSF1 from repression of its transcriptional activity by HSP90-dependent multichaperone complex upon heat shock (PubMed:15016915). Interacts (via D domain and preferentially with hyperphosphorylated form) with JNK1; this interaction occurs under both normal growth conditions and immediately upon heat shock (PubMed:10747973). Interacts (via D domain and preferentially with hyperphosphorylated form) with MAPK3; this interaction occurs upon heat shock (PubMed:10747973). Interacts with IER5 (via central region); this interaction promotes PPP2CA-induced dephosphorylation on Ser-121, Ser-307, Ser-314, Thr-323 and Thr-367 and HSF1 transactivation activity (PubMed:25816751, PubMed:26496226, PubMed:26754925). Found in a ribonucleoprotein complex composed of the HSF1 homotrimeric form, translation elongation factor eEF1A proteins and non-coding RNA heat shock RNA-1 (HSR1); this complex occurs upon heat shock and stimulates HSF1 DNA-binding activity (PubMed:16554823). Interacts (via transactivation domain) with HSPA1A/HSP70 and DNAJB1; these interactions result in the inhibition of heat shock- and HSF1-induced transcriptional activity during the attenuation and recovery phase from heat shock (PubMed:7935376, PubMed:9222587, PubMed:9499401). Interacts (via Ser-303 and Ser-307 phosphorylated form) with YWHAE; this interaction promotes HSF1 sequestration in the cytoplasm in an ERK-dependent manner (PubMed:12917326). Found in a complex with IER5 and PPP2CA (PubMed:26754925). Interacts with TPR; this interaction increases upon heat shock and stimulates export of HSP70 mRNA (PubMed:17897941). Interacts with SYMPK (via N-terminus) and CSTF2; these interactions occur upon heat shock (PubMed:14707147). Interacts (via transactivation domain) with HSPA8 (PubMed:9499401). Interacts with EEF1D; this interaction occurs at heat shock promoter element (HSE) sequences (PubMed:21597468). Interacts with MAPKAPK2 (PubMed:16278218). Interacts with PRKACA/PKA (PubMed:21085490). Interacts (via transactivation domain) with GTF2A2 (PubMed:11005381). Interacts (via transactivation domain) with GTF2B (PubMed:11005381). Interacts (via transactivation domain) with TBP (PubMed:11005381). Interacts with CDK9, CCNT1 and EP300 (PubMed:27189267). Interacts (via N-terminus) with XRCC5 (via N-terminus) and XRCC6 (via N-terminus); these interactions are direct and prevent XRCC5/XRCC6 heterodimeric binding and non-homologous end joining (NHEJ) repair activities induced by ionizing radiation (IR) (PubMed:26359349). Interacts with PLK1; this interaction occurs during the early mitotic period, increases upon heat shock but does not modulate neither HSF1 homotrimerization and DNA-binding activities (PubMed:15661742, PubMed:18794143). Interacts (via Ser-216 phosphorylated form) with CDC20; this interaction occurs in mitosis in a MAD2L1-dependent manner and prevents PLK1-stimulated degradation of HSF1 by blocking the recruitment of the SCF(BTRC) ubiquitin ligase complex (PubMed:18794143). Interacts with MAD2L1; this interaction occurs in mitosis (PubMed:18794143). Interacts with BTRC; this interaction occurs during mitosis, induces its ubiquitin-dependent degradation following stimulus-dependent phosphorylation at Ser-216, a process inhibited by CDC20 (PubMed:18794143). Interacts with HSP90AA1 and HSP90AB1 (PubMed:26517842).DOMAIN In unstressed cells, spontaneous homotrimerization is inhibited (PubMed:7935471, PubMed:7760831). Intramolecular interactions between the hydrophobic repeat HR-A/B and HR-C regions are necessary to maintain HSF1 in the inactive, monomeric conformation (PubMed:7935471, PubMed:7623826). Furthermore, intramolecular interactions between the regulatory domain and the nonadjacent transactivation domain prevents transcriptional activation, a process that is relieved upon heat shock (PubMed:7760831). The regulatory domain is necessary for full repression of the transcriptional activation domain in unstressed cells through its phosphorylation on Ser-303 and Ser-307 (PubMed:8946918, PubMed:9121459). In heat stressed cells, HSF1 homotrimerization occurs through formation of a three-stranded coiled-coil structure generated by intermolecular interactions between HR-A/B regions allowing DNA-binding activity (PubMed:7935471). The D domain is necessary for translocation to the nucleus, interaction with JNK1 and MAPK3 and efficient JNK1- and MAPK3-dependent phosphorylation (PubMed:10747973). The regulatory domain confers heat shock inducibility on the transcriptional transactivation domain (PubMed:7760831). The regulatory domain is necessary for transcriptional activation through its phosphorylation on Ser-230 upon heat shock (PubMed:11447121). 9aaTAD is a transactivation motif present in a large number of yeast and animal transcription factors (PubMed:17467953).PTM Phosphorylated (PubMed:9499401, PubMed:10359787, PubMed:11583998, PubMed:26159920). Phosphorylated in unstressed cells; this phosphorylation is constitutive and implicated in the repression of HSF1 transcriptional activity (PubMed:8946918, PubMed:8940068, PubMed:9121459, PubMed:16278218). Phosphorylated on Ser-121 by MAPKAPK2; this phosphorylation promotes interaction with HSP90 proteins and inhibits HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Phosphorylation on Ser-303 by GSK3B/GSK3-beta and on Ser-307 by MAPK3 within the regulatory domain is involved in the repression of HSF1 transcriptional activity and occurs in a RAF1-dependent manner (PubMed:8946918, PubMed:8940068, PubMed:9121459, PubMed:9535852, PubMed:10747973, PubMed:12646186). Phosphorylation on Ser-303 and Ser-307 increases HSF1 nuclear export in a YWHAE- and XPO1/CRM1-dependent manner (PubMed:12917326). Phosphorylation on Ser-307 is a prerequisite for phosphorylation on Ser-303 (PubMed:8940068). According to PubMed:9535852, Ser-303 is not phosphorylated in unstressed cells. Phosphorylated on Ser-419 by PLK1; phosphorylation promotes nuclear translocation upon heat shock (PubMed:15661742). Hyperphosphorylated upon heat shock and during the attenuation and recovery phase period of the heat shock response (PubMed:11447121, PubMed:12659875, PubMed:24581496). Phosphorylated on Thr-142; this phosphorylation increases HSF1 transactivation activity upon heat shock (PubMed:12659875). Phosphorylation on Ser-230 by CAMK2A; this phosphorylation enhances HSF1 transactivation activity upon heat shock (PubMed:11447121). Phosphorylation on Ser-326 by MAPK12; this phosphorylation enhances HSF1 nuclear translocation, homotrimerization and transactivation activities upon heat shock (PubMed:15760475, PubMed:27354066). Phosphorylated on Ser-320 by PRKACA/PKA; this phosphorylation promotes nuclear localization and transcriptional activity upon heat shock (PubMed:21085490). Phosphorylated on Ser-363 by MAPK8; this phosphorylation occurs upon heat shock, induces HSF1 translocation into nuclear stress bodies and negatively regulates transactivation activity (PubMed:10747973). Neither basal nor stress-inducible phosphorylation on Ser-230, Ser-292, Ser-303, Ser-307, Ser-314, Ser-319, Ser-320, Thr-323, Ser-326, Ser-338, Ser-344, Ser-363, Thr-367, Ser-368 and Thr-369 within the regulatory domain is involved in the regulation of HSF1 subcellular localization or DNA-binding activity; however, it negatively regulates HSF1 transactivation activity (PubMed:25963659). Phosphorylated on Ser-216 by PLK1 in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex inducing HSF1 degradation, and hence mitotic progression (PubMed:18794143). Dephosphorylated on Ser-121, Ser-307, Ser-314, Thr-323 and Thr-367 by phosphatase PPP2CA in an IER5-dependent manner, leading to HSF1-mediated transactivation activity (PubMed:26754925).PTM Sumoylated with SUMO1 and SUMO2 upon heat shock in a ERK2-dependent manner (PubMed:12646186, PubMed:12665592). Sumoylated by SUMO1 on Lys-298; sumoylation occurs upon heat shock and promotes its localization to nuclear stress bodies and DNA-binding activity (PubMed:11514557). Phosphorylation on Ser-303 and Ser-307 is probably a prerequisite for sumoylation (PubMed:12646186, PubMed:12665592).PTM Acetylated on Lys-118; this acetylation is decreased in a IER5-dependent manner (PubMed:26754925). Acetylated on Lys-118, Lys-208 and Lys-298; these acetylations occur in a EP300-dependent manner (PubMed:24581496, PubMed:27189267). Acetylated on Lys-80; this acetylation inhibits DNA-binding activity upon heat shock (PubMed:19229036). Deacetylated on Lys-80 by SIRT1; this deacetylation increases DNA-binding activity (PubMed:19229036).PTM Ubiquitinated by SCF(BTRC) and degraded following stimulus-dependent phosphorylation at Ser-216 by PLK1 in mitosis (PubMed:18794143). Polyubiquitinated (PubMed:24581496). Undergoes proteasomal degradation upon heat shock and during the attenuation and recovery phase period of the heat shock response (PubMed:24581496).SIMILARITY Belongs to the HSF family.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtQ00613

Inter-chain Crosslink via L-cystine (cross-link) at 103 and 36

103

EQUAL

L-cystine (cross-link)ChEBI50058

modification

Inter-chain Crosslink via L-cystine (cross-link) at 36 and 103

EQUAL

Chain Coordinates

EQUAL

529

EQUAL

Reactome Database ID Release 754793790Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4793790ReactomeR-HSA-4793790

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4793790.1

Reactome DB_ID: 29358

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 5082354

p-S326-HSF1 trimer [nucleoplasm]

p-S326-HSF1 trimer

Reactome DB_ID: 5082355

Inter-chain Crosslink via L-cystine (cross-link) at 103 and 36

103

EQUAL

Inter-chain Crosslink via L-cystine (cross-link) at 36 and 103

EQUAL

O-phospho-L-serine at 326

326

EQUAL

O-phospho-L-serine [MOD:00046]

EQUAL

529

EQUAL

Reactome Database ID Release 755082354Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082354ReactomeR-HSA-5082354

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082354.1

Reactome DB_ID: 113582

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 5083643

mTORC1 dimer [nucleoplasm]

mTORC1 dimer

Reactome DB_ID: 5083661

MLST8:MTOR:RPTOR:AKT1S1 [nucleoplasm]

MLST8:MTOR:RPTOR:AKT1S1

mTORC1

Reactome DB_ID: 5083646

UniProt:Q9BVC4 MLST8

MLST8

GBLMLST8LST8FUNCTION Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts directly with MTOR and RPTOR. Interacts with RHEB. Interacts with MEAK7 (PubMed:29750193). Interacts with SIK3 (PubMed:30232230).TISSUE SPECIFICITY Broadly expressed, with highest levels in skeletal muscle, heart and kidney.SIMILARITY Belongs to the WD repeat LST8 family.

UniProtQ9BVC4

EQUAL

326

EQUAL

Reactome DB_ID: 5083637

UniProt:Q96B36 AKT1S1

AKT1S1

PRAS40AKT1S1FUNCTION Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Interacts directly with RPTOR. The phosphorylated form interacts with 14-3-3 proteins.TISSUE SPECIFICITY Widely expressed with highest levels of expression in liver and heart. Expressed at higher levels in cancer cell lines (e.g. A-549 and HeLa) than in normal cell lines (e.g. HEK293).PTM Phosphorylated by AKT1 (PubMed:12524439). Phosphorylation at Thr-246 by DYRK3 relieves inhibitory function on mTORC1 (PubMed:23415227).

UniProtQ96B36

EQUAL

256

EQUAL

Reactome DB_ID: 5083674

UniProt:P42345 MTOR

MTOR

FRAP1RAFT1FRAP2FRAPRAPT1MTORFUNCTION Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12150925, PubMed:12087098, PubMed:18925875). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity).ACTIVITY REGULATION Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1. Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1. Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906). On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. The mTORC1 complex is a 1 Md obligate dimer of two stoichiometric heterotetramers with overall dimensions of 290 A x 210 A x 135 A. It has a rhomboid shape and a central cavity, the dimeric interfaces are formed by interlocking interactions between the two MTOR and the two RPTOR subunits. The MLST8 subunit forms distal foot-like protuberances, and contacts only one MTOR within the complex, while the small PRAS40 localizes to the midsection of the central core, in close proximity to RPTOR. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with PLPP7 and PML. Interacts with PRR5 and RICTOR; the interaction is direct within the mTORC2 complex. Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with UBQLN1. Interacts with TTI1 and TELO2. Interacts with CLIP1; phosphorylates and regulates CLIP1. Interacts with NBN. Interacts with HTR6 (PubMed:23027611). Interacts with BRAT1. Interacts with MEAK7 (via C-terminal domain); the interaction increases upon nutrient stimulation (PubMed:29750193). Interacts with TM4SF5; the interaction is positively regulated by arginine and is negatively regulated by leucine (PubMed:30956113). Interacts with GPR137B (PubMed:31036939).TISSUE SPECIFICITY Expressed in numerous tissues, with highest levels in testis.DOMAIN The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.DOMAIN The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (PubMed:23636326).PTM Autophosphorylates when part of mTORC1 or mTORC2. Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation. Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and PRAS40 and leads to increased intrinsic mTORC1 kinase activity. Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity.SIMILARITY Belongs to the PI3/PI4-kinase family.

UniProtP42345

EQUAL

2549

EQUAL

Reactome DB_ID: 5083664

UniProt:Q8N122 RPTOR

RPTOR

RPTORRAPTORKIAA1303FUNCTION Involved in the control of the mammalian target of rapamycin complex 1 (mTORC1) activity which regulates cell growth and survival, and autophagy in response to nutrient and hormonal signals; functions as a scaffold for recruiting mTORC1 substrates. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Involved in ciliogenesis.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR (PubMed:12150925, PubMed:12408816, PubMed:17386266, PubMed:25940091). mTORC1 binds to and is inhibited by FKBP12-rapamycin (PubMed:12408816, PubMed:15066126). Binds directly to 4EBP1 and RPS6KB1 independently of its association with MTOR (PubMed:12150925, PubMed:12150926). Binds preferentially to poorly or non-phosphorylated forms of EIF4EBP1, and this binding is critical to the ability of MTOR to catalyze phosphorylation (PubMed:12747827). Forms a complex with MTOR under both leucine-rich and -poor conditions. Interacts with ULK1 in a nutrient-dependent manner; the interaction is reduced during starvation (PubMed:19211835). Interacts (when phosphorylated by AMPK) with 14-3-3 protein, leading to inhibition of its activity (PubMed:18439900). Interacts with SPAG5; SPAG5 competes with MTOR for RPTOR-binding, resulting in decreased mTORC1 formation. Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with G3BP1. The complex formed with G3BP1 AND SPAG5 is increased by oxidative stress (PubMed:23953116). Interacts with HTR6 (PubMed:23027611). Interacts with PIH1D1 (PubMed:24036451). Interacts with LARP1 (PubMed:25940091). Interacts with BRAT1 (PubMed:25657994). Interacts with SIK3 (PubMed:30232230).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.TISSUE SPECIFICITY Highly expressed in skeletal muscle, and in a lesser extent in brain, lung, small intestine, kidney and placenta. Isoform 3 is widely expressed, with highest levels in nasal mucosa and pituitary and lowest in spleen.PTM Insulin-stimulated phosphorylation at Ser-863 by MTOR and MAPK8 up-regulates mTORC1 activity. Osmotic stress also induces phosphorylation at Ser-696, Thr-706 and Ser-863 by MAPK8. Ser-863 phosphorylation is required for phosphorylation at Ser-855 and Ser-859. In response to nutrient limitation, phosphorylated by AMPK; phosphorylation promotes interaction with 14-3-3 proteins, leading to negative regulation of the mTORC1 complex. In response to growth factors, phosphorylated at Ser-719, Ser-721 and Ser-722 by RPS6KA1, which stimulates mTORC1 activity.SIMILARITY Belongs to the WD repeat RAPTOR family.

UniProtQ8N122

EQUAL

1335

EQUAL

Reactome Database ID Release 755083661Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5083661ReactomeR-HSA-5083661

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5083661.1Reactome Database ID Release 755083643Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5083643ReactomeR-HSA-5083643

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5083643.2GO0004674

GO molecular function

Reactome Database ID Release 755083660Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5083660Reactome Database ID Release 755082405Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082405ReactomeR-HSA-5082405

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082405.222768106Pubmed2012mTOR is essential for the proteotoxic stress response, HSF1 activation and heat shock protein synthesisChou, Shiuh-DihPrince, TGong, JianlinCalderwood, Stuart KPLoS ONE 7:e3967915760475Pubmed2005Analysis of phosphorylation of human heat shock factor 1 in cells experiencing a stressGuettouche, ToumyBoellmann, FrankLane, William SVoellmy, RichardBMC Biochem. 6:420605781Pubmed2010mTORC1 links protein quality and quantity control by sensing chaperone availabilityQian, Shu-BingZhang, XingqianSun, JunBennink, Jack RYewdell, Jonathan WPatterson, CJ. Biol. Chem. 285:27385-95

2.7.11

Phosphorylation of HSF1 at Ser230 induces transactivation

The transcriptional activity of HSF1 has been shown to be controlled by the regulatory domain composed of amino acids 221-310 (Green M et al. 1995; Zuo J et al. 1995; Newton EM et al., 1996). Ser230 is located in this regulatory domain of HSF1 and is constitutively and stress-inducibly phosphorylated (Holmberg CI et al. 2001). Analyses with phosphopeptide-specific antibody and site-directed mutagenesis revealed that phosphorylation at Ser230 enhanced the inducible HSF1 transcriptional activity in heat-shocked human K562 erythroleukemia and HeLa cells (Holmberg CI et al 2001). Active calcium/calmodulin-dependent protein kinase II (CaMKII) was shown to phosphorylate HSF1 at Ser230 in vitro. Moreover, CaMKII enhanced heat-induced tranactivating capacity of HSF1 and the level of endogenous Ser230 phosphorylation in K562 cells transfected with active CaMKII together with a CAT reporter plasmid containing the proximal HSE of human hsp70 promoter. Thus, CaMKII signaling may be involved in the positive regulation of HSF1-mediated transactivation. However, the possibility that other protein kinases might also phosphorylate Ser230 in vivo should not be excluded (Holmberg CI et al 2001).

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 4793790

Reactome DB_ID: 29358

Reactome DB_ID: 5082353

p-S230-HSF1 trimer [nucleoplasm]

p-S230-HSF1 trimer

Reactome DB_ID: 5082361

Inter-chain Crosslink via L-cystine (cross-link) at 103 and 36

103

EQUAL

Inter-chain Crosslink via L-cystine (cross-link) at 36 and 103

EQUAL

O-phospho-L-serine at 230

230

EQUAL

529

EQUAL

Reactome Database ID Release 755082353Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082353ReactomeR-HSA-5082353

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082353.1

Reactome DB_ID: 113582

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 444796

CaMKII [nucleoplasm]

CaMKII

Converted from EntitySet in Reactome

Reactome DB_ID: 9007035

p-CAMK2A, p-CAMK2B [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T286-CAMK2A [nucleoplasm]p-T287-CAMK2B [nucleoplasm]

UniProtQ9UQM7UniProtQ13554Converted from EntitySet in Reactome

Reactome DB_ID: 9007033

p-CAMK2D, p-CAMK2G [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T287-CAMK2D [nucleoplasm]p-T287-CAMK2G [nucleoplasm]

UniProtQ13557UniProtQ13555Reactome Database ID Release 75444796Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=444796ReactomeR-HSA-444796

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-444796.2Reactome Database ID Release 755082383Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082383Reactome Database ID Release 755082387Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082387ReactomeR-HSA-5082387

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082387.17760831Pubmed1995A heat shock-responsive domain of human HSF1 that regulates transcription activation domain functionGreen, MSchuetz, T JSullivan, E KKingston, R EMol. Cell. Biol. 15:3354-627623826Pubmed1995Multiple layers of regulation of human heat shock transcription factor 1Zuo, JRungger, DVoellmy, RMol. Cell. Biol. 15:4319-308622685Pubmed1996The regulatory domain of human heat shock factor 1 is sufficient to sense heat stressNewton, E MKnauf, UGreen, MKingston, R EMol. Cell. Biol. 16:839-4611447121Pubmed2001Phosphorylation of serine 230 promotes inducible transcriptional activity of heat shock factor 1Holmberg, C IHietakangas, VMikhailov, ARantanen, J OKallio, MMeinander, AHellman, JMorrice, NMacKintosh, CMorimoto, R IEriksson, J ESistonen, LEMBO J. 20:3800-10

HSF1-mediated gene expression

Combination of chromatin immunoprecipitation (ChIP) microarray analysis and time course gene expression microarray analysis with and without siRNA-mediated inhibition of HSF1 showed that human HSF1 can induce the expression of different sets of target genes to maintain a wide range of biological processes (e.g., anti-apoptosis, RNA splicing, ubiquitination)(Page TG et al. 2006; Vihervaara A. et al. 2013). However, HSF1 is best known for rapid stress-induced upregulation of certain genes related to protein folding, such as HSPA1A/HSP70, HSPC/HSP90, HSPB1/HSP27, and DNAJB1/HSP40 (Mosser DD et al. 1988; Trinklein ND et al. 2004a,b; Page TG et al. 2006; Vihervaara A. et al. 2013).In the nucleus acetylation of Histone H3 is linked to the function of the Elongator complex in transcription (Kim JH et al. 2002). Elongator complex protein 3 (ELP3), a catalytic acetyltransferase subunit of the Elongator complex, has been reported to regulate the transcription of HSP70 gene, and the histone acetyltransferase (HAT) domain of ELP3 is essential for this function (Han Q et al. 2007; Li F et al. 2001).

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 4793813

HSF1 trimer:target gene [nucleoplasm]

HSF1 trimer:target gene

Reactome DB_ID: 4793790

Converted from EntitySet in Reactome

Reactome DB_ID: 4793834

HSF1 target gene [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHSPH1 gene [nucleoplasm]HSPA1B gene [nucleoplasm]HSPA1L gene [nucleoplasm]HSPA1L gene [nucleoplasm]HSBP2 gene [nucleoplasm]HSPA1L gene [nucleoplasm]UBB gene [nucleoplasm]HSPA1L gene [nucleoplasm]HSPA1A gene [nucleoplasm]DNAJB6 gene [nucleoplasm]HSPA6 gene [nucleoplasm]CRYBA4 gene [nucleoplasm]HSPA1B gene [nucleoplasm]HSPA1A gene [nucleoplasm]HSPA1B gene [nucleoplasm]HSPA1A gene [nucleoplasm]HSPA1A gene [nucleoplasm]HSBP2 gene [nucleoplasm]GML gene [nucleoplasm]MRPL18 gene [nucleoplasm]HSPA1A gene [nucleoplasm]DNAJB1 gene [nucleoplasm]HSBP1 gene [nucleoplasm]RLN1 gene [nucleoplasm]HSPA1B gene [nucleoplasm]HSPA1B gene [nucleoplasm]FKBP4 gene [nucleoplasm]SERPINH1 gene [nucleoplasm]COL4A6 gene [nucleoplasm]TNFRSF21 gene [nucleoplasm]DEDD2 gene [nucleoplasm]

ENSEMBLENSG00000120694ENSEMBLENSG00000204388ENSEMBLENSG00000226704ENSEMBLENSG00000236251ENSEMBLENSG00000262852ENSEMBLENSG00000206383ENSEMBLENSG00000170315ENSEMBLENSG00000234258ENSEMBLENSG00000215328ENSEMBLENSG00000105993ENSEMBLENSG00000173110ENSEMBLENSG00000196431ENSEMBLENSG00000212866ENSEMBLENSG00000204389ENSEMBLENSG00000224501ENSEMBLENSG00000234475ENSEMBLENSG00000237724ENSEMBLENSG00000170276ENSEMBLENSG00000104499ENSEMBLENSG00000112110ENSEMBLENSG00000235941ENSEMBLENSG00000132002ENSEMBLENSG00000106211ENSEMBLENSG00000107018ENSEMBLENSG00000232804ENSEMBLENSG00000231555ENSEMBLENSG00000004478ENSEMBLENSG00000149257ENSEMBLENSG00000197565ENSEMBLENSG00000146072ENSEMBLENSG00000160570Reactome Database ID Release 754793813Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4793813ReactomeR-HSA-4793813

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4793813.1Converted from EntitySet in Reactome

Reactome DB_ID: 5096380

Heat shock inducible proteins [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHSPA8 [nucleoplasm]CRYAB [nucleoplasm]HSBP1 [nucleoplasm]HSPA1L [nucleoplasm]DNAJB1 [nucleoplasm]HSP90AA1 [nucleoplasm]HSP90AB1 [nucleoplasm]HSPA1A [nucleoplasm]HSPA1B [nucleoplasm]HSPB8 [nucleoplasm]

UniProtP11142UniProtP02511UniProtO75506UniProtP34931UniProtP25685UniProtP07900UniProtP08238UniProtP0DMV8UniProtP0DMV9UniProtQ9UJY1Reactome Database ID Release 755082356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082356ReactomeR-HSA-5082356

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082356.23211126Pubmed1988Coordinate changes in heat shock element-binding activity and HSP70 gene transcription rates in human cellsMosser, D DTheodorakis, N GMorimoto, R IMol. Cell. Biol. 8:4736-4417558451Pubmed2007hELP3 subunit of the Elongator complex regulates the transcription of HSP70 gene in human cellsHan, QiujuHou, XiaozheSu, DongmeiPan, LinaDuan, JizhouCui, LiguoHuang, BaiquLu, JunActa Biochim. Biophys. Sin. (Shanghai) 39:453-6117216044Pubmed2006Genome-wide analysis of human HSF1 signaling reveals a transcriptional program linked to cellular adaptation and survivalPage, Todd JSikder, DevanjanYang, LonglongPluta, LindaWolfinger, Russell DKodadek, ThomasThomas, Russell SMol Biosyst 2:627-3915270074Pubmed2004Transcriptional regulation and binding of heat shock factor 1 and heat shock factor 2 to 32 human heat shock genes during thermal stress and differentiationTrinklein, Nathan DChen, Will CKingston, Robert EMyers, Richard MCell Stress Chaperones 9:21-811818576Pubmed2002Human Elongator facilitates RNA polymerase II transcription through chromatinKim, Jae-HyunLane, William SReinberg, DannyProc. Natl. Acad. Sci. U.S.A. 99:1241-68455624Pubmed1993Activation of human heat shock genes is accompanied by oligomerization, modification, and rapid translocation of heat shock transcription factor HSF1Baler, RDahl, GVoellmy, RMol. Cell. Biol. 13:2486-9614668476Pubmed2004The role of heat shock transcription factor 1 in the genome-wide regulation of the mammalian heat shock responseTrinklein, Nathan DMurray, John IHartman, Sara JBotstein, DavidMyers, Richard MMol. Biol. Cell 15:1254-6122216241Pubmed2011hElp3 directly modulates the expression of HSP70 gene in HeLa cells via HAT activityLi, FenMa, JixianMa, YuHu, YanyanTian, ShujuanWhite, Richard EHan, GuichunPLoS ONE 6:e2930323959860Pubmed2013Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cellsVihervaara, AnniinaSergelius, ChristianVasara, JenniBlom, Malin A HElsing, Alexandra NRoos-Mattjus, PiaSistonen, LeaProc. Natl. Acad. Sci. U.S.A. 110:E3388-97

ACTIVATION

Reactome Database ID Release 755082359Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082359ReactomeR-HSA-5082359

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082359.1

Reactome DB_ID: 5082354

ACTIVATION

Reactome Database ID Release 755082358Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082358ReactomeR-HSA-5082358

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082358.1

Reactome DB_ID: 5082353

Attenuation phase

Attenuation of the heat shock transcriptional response occurs during continuous exposure to intermediate heat shock conditions or upon recovery from stress (Abravaya et al. 1991). The attenuation phase of HSF1 cycle involves the transcriptional silencing of HSF1 bound to HSE, the release of HSF1 trimers from HSE and dissociation of HSF1 trimers to monomers. HSF1-driven heat stress associated transcription was shown to depend on inducible and reversible acetylation of HSF1 at Lys80, which negatively regulates DNA binding activity of HSF1 (Westerheide SD et al. 2009). In addition, the attenuation of HSF1 activation takes place when enough HSP70/HSP40 is produced to saturate exposed hydrophobic regions of proteins damaged as a result of heat exposure. The excess HSP70/HSP40 binds to HSF1 trimer, which leads to its dissociation from the promoter and conversion to the inactive monomeric form (Abravaya et al. 1991; Shi Y et al. 1998). Interaction of HSP70 with the transcriptional corepressor repressor element 1-silencing transcription factor corepressor (CoREST) assists in terminating heat-shock response (Gomez AV et al. 2008). HSF1 DNA-binding and transactivation activity were also inhibited upon interaction of HSF1-binding protein (HSBP1) with active trimeric HSF1(Satyal SH et al. 1998).

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

HSP70:DNAJB1 binds HSF1

During attenuation and recovery from heat shock, increased levels of HSP70 and HDJ1 (HSP40) were found to associate with the HSF1 activation domain, repressing its transcriptional activity (Shi Y et al. 1998)

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 4793813

Reactome DB_ID: 5082372

HSP70:DNAJB1 [nucleoplasm]

HSP70:DNAJB1

Reactome DB_ID: 5082374

DNAJB1 dimer [nucleoplasm]

DNAJB1 dimer

Reactome DB_ID: 5082366

UniProt:P25685 DNAJB1

DNAJB1

DNAJB1HDJ1DNAJ1HSPF1FUNCTION Interacts with HSP70 and can stimulate its ATPase activity. Stimulates the association between HSC70 and HIP. Negatively regulates heat shock-induced HSF1 transcriptional activity during the attenuation and recovery phase period of the heat shock response (PubMed:9499401). Stimulates ATP hydrolysis and the folding of unfolded proteins mediated by HSPA1A/B (in vitro) (PubMed:24318877).SUBUNIT Interacts with DNAJC3 (PubMed:9920933). Interacts with HSF1 (via transactivation domain); this interaction results in the inhibition of heat shock- and HSF1-induced transcriptional activity during the attenuation and recovery phase period of the heat shock response (PubMed:9499401).INDUCTION By heat shock.

EQUAL

340

EQUAL

Reactome Database ID Release 755082374Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082374ReactomeR-HSA-5082374

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082374.1Converted from EntitySet in Reactome

Reactome DB_ID: 5082379

HSPA (HSP70) proteins [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHSPA8 [nucleoplasm]HSPA1A [nucleoplasm]HSPA1B [nucleoplasm]

Reactome Database ID Release 755082372Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082372ReactomeR-HSA-5082372

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082372.1

Reactome DB_ID: 5082415

HSP70:DNAJB1:HSF1 trimer:target gene [nucleoplasm]

HSP70:DNAJB1:HSF1 trimer:target gene

Reactome DB_ID: 4793813

Reactome DB_ID: 5082372

Reactome Database ID Release 755082415Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082415ReactomeR-HSA-5082415

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082415.1Reactome Database ID Release 755082384Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082384ReactomeR-HSA-5082384

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082384.19499401Pubmed1998Molecular chaperones as HSF1-specific transcriptional repressorsShi, YMosser, D DMorimoto, R IGenes Dev. 12:654-661607379Pubmed1992Heat shock gene regulation by nascent polypeptides and denatured proteins: hsp70 as a potential autoregulatory factorBaler, RWelch, W JVoellmy, RJ. Cell Biol. 117:1151-91628823Pubmed1992The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expressionAbravaya, KMyers, M PMurphy, S PMorimoto, R IGenes Dev. 6:1153-64

HSF1 acetylation at Lys80

Acetylated HSF1 was detected in lysates of human embryonic kidney 293T cells which were transfected with vectors encoding a Flag-HSF1 fusion and p300 proteins and exposed to various stress conditions (Westerheide SD et al. 2012). No acetylation was found in lysates of unstressed cells. Acetylation of HSF1 may occurs on multiple lysines, such as Lys80 within the DNA binding domain. Mutation of Lys80 disrupted the DNA-binding ability of recombinant HSF1, indicating that the acetylation at Lys80 caused the regulated release of the HSF1 trimers from DNA and thus represents a regulatory step in the attenuation of the heat shock responce (Westerheide SD et al. 2009; Herbomel G et al 2013).

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 5082415

Reactome DB_ID: 113560

acetyl-CoA [ChEBI:15351]

acetyl-CoA

ChEBI15351

Reactome DB_ID: 5082373

HSP70:DNAJB1:Ac-K80-HSF1 trimer:target gene [nucleoplasm]

HSP70:DNAJB1:Ac-K80-HSF1 trimer:target gene

Reactome DB_ID: 5097240

Ac-K80-HSF1 trimer [nucleoplasm]

Ac-K80-HSF1 trimer

Reactome DB_ID: 5097238

Inter-chain Crosslink via L-cystine (cross-link) at 103 and 36

103

EQUAL

Inter-chain Crosslink via L-cystine (cross-link) at 36 and 103

EQUAL

N6-acetyl-L-lysine at 80

EQUAL

N6-acetyl-L-lysine [MOD:00064]

EQUAL

529

EQUAL

Reactome Database ID Release 755097240Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5097240ReactomeR-HSA-5097240

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5097240.1

Reactome DB_ID: 5082372

Converted from EntitySet in Reactome

Reactome DB_ID: 4793834

Reactome Database ID Release 755082373Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082373ReactomeR-HSA-5082373

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082373.1

Reactome DB_ID: 2485002

coenzyme A [ChEBI:15346]

coenzyme A

ChEBI15346PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 1027362

CREBBP,EP300 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityEP300 [nucleoplasm]CREBBP [nucleoplasm]

UniProtQ09472UniProtQ92793GO0034212

GO molecular function

Reactome Database ID Release 755083648Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5083648Reactome Database ID Release 753371554Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3371554ReactomeR-HSA-3371554

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371554.123861773Pubmed2013Dynamics of the full length and mutated heat shock factor 1 in human cellsHerbomel, GaëtanKloster-Landsberg, MeikeFolco, Eric GCol, EdwigeUsson, YvesVourc'h, ClaireDelon, AntoineSouchier, CatherinePLoS ONE 8:e6756619229036Pubmed2009Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1Westerheide, Sandy DAnckar, JuliusStevens, Stanley MSistonen, LeaMorimoto, Richard IScience 323:1063-6

Acetylated HSF1 dissociates from DNA

Inducible acetylation of HSF1 at Lys80 within the DNA binding domain results in the disrupted DNA-binding ability thus causing the regulated release of the HSF1 trimers from DNA (Westerheide SD et al. 2009). This acetylation is reversible. Activation of the deacetylase and longevity factor SIRT1 was shown to prolong HSF1 binding to the heat shock promoter of hsp70 gene by maintaining HSF1 in a deacetylated state (Westerheide SD et al. 2009). Thus, the balance between deacetylase activity of SIRT1 and acetyltransferase activity of p300 determine the DNA-binding competent state of HSF1.

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 5082373

Reactome DB_ID: 5082365

HSP70:DNAJB1:Ac-K80-HSF1 [nucleoplasm]

HSP70:DNAJB1:Ac-K80-HSF1

Reactome DB_ID: 5097240

Reactome DB_ID: 5082372

Reactome Database ID Release 755082365Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082365ReactomeR-HSA-5082365

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082365.1Converted from EntitySet in Reactome

Reactome DB_ID: 4793834

Reactome Database ID Release 755082369Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082369ReactomeR-HSA-5082369

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082369.1

HSBP1 binds HSF1 trimer

Heat shock factor binding protein 1 (HSBP1) is a nuclear localized hydrophobic repeat-containing protein, which interacts with trimerization domain of HSF1 and negatively regulates DNA-binding activity of HSF1. Overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1 (Satyal SH et al. 1998).

Authored: Shamovsky, V, 2013-10-28Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 4793790

Reactome DB_ID: 3371426

HSBP1 hexamer [nucleoplasm]

HSBP1 hexamer

Reactome DB_ID: 3371551

HSBP1 trimer [nucleoplasm]

HSBP1 trimer

Reactome DB_ID: 3371589

UniProt:O75506 HSBP1

HSBP1

HSBP1HSF1BPFUNCTION Negative regulator of the heat shock response. Negatively affects HSF1 DNA-binding activity. May have a role in the suppression of the activation of the stress response during the aging process.SUBUNIT Homohexamer. Associates with heptad repeats of HSF1 trimers and probably also HSF1 monomers, and with HSP70. Association with HSF1 trimers and HSP70 coincides with attenuation of heat shock response and the conversion of HSF1 trimer to monomer.SIMILARITY Belongs to the HSBP1 family.

EQUAL

Reactome Database ID Release 753371551Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3371551ReactomeR-HSA-3371551

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371551.1Reactome Database ID Release 753371426Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3371426ReactomeR-HSA-3371426

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371426.1

Reactome DB_ID: 5082413

HSBP1:HSF1 trimer [nucleoplasm]

HSBP1:HSF1 trimer

Reactome DB_ID: 4793790

Reactome DB_ID: 3371426

Reactome Database ID Release 755082413Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5082413ReactomeR-HSA-5082413

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5082413.1Reactome Database ID Release 753371582Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3371582ReactomeR-HSA-3371582

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371582.19649501Pubmed1998Negative regulation of the heat shock transcriptional response by HSBP1Satyal, S HChen, DFox, S GKramer, J MMorimoto, R IGenes Dev. 12:1962-74

HSP90:FKBP4:PTGES3 binds HSF1 trimer

Under non-stress conditions monomeric HSF1 is sequestered in a HSP90-containing heterocomplex. FKBP4 (immunophilin) is one of the components of HSP90-chaperone machinery which was found to associate with trimeric, but not monomeric form of HSF1 (Guo Y et al. 2001). Multichaperone complex of HSP90:FKBP4:PKGES3 has been shown to associate with HSF1 trimer through its regulatory domain, and this is thought to repress HSF1 transcriptional activity (Guo Y et al. 2001).

Authored: Shamovsky, V, 2013-11-18Reviewed: Pani, Bibhusita, 2014-02-17Edited: Shamovsky, V, 2014-02-17

Reactome DB_ID: 5324622

HSP90:FKBP4:PTGES3 [nucleoplasm]

HSP90:FKBP4:PTGES3

Reactome DB_ID: 5324621

UniProt:Q02790 FKBP4

FKBP4

FKBP52FKBP4FUNCTION Immunophilin protein with PPIase and co-chaperone activities. Component of steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments. The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.ACTIVITY REGULATION Inhibited by FK506.SUBUNIT Homodimer (By similarity). Interacts with GLMN (PubMed:12604780). Associates with HSP90AA1 and HSP70 in steroid hormone receptor complexes. Also interacts with peroxisomal phytanoyl-CoA alpha-hydroxylase (PHYH). Interacts with NR3C1 and dynein. Interacts with HSF1 in the HSP90 complex. Associates with tubulin. Interacts with MAPT/TAU (By similarity). Interacts (via TPR domain) with S100A1, S100A2 and S100A6; the interaction is Ca(2+) dependent. Interaction with S100A1 and S100A2 (but not with S100A6) leads to inhibition of FKBP4-HSP90 interaction. Interacts with dynein; causes partially NR3C1 transport to the nucleus.TISSUE SPECIFICITY Widely expressed.DOMAIN The PPIase activity is mainly due to the first PPIase FKBP-type domain (1-138 AA).DOMAIN The C-terminal region (AA 375-458) is required to prevent tubulin polymerization.DOMAIN The chaperone activity resides in the C-terminal region, mainly between amino acids 264 and 400.DOMAIN The TPR repeats mediate mitochondrial localization.PTM Phosphorylation by CK2 results in loss of HSP90 binding activity.

UniProtQ02790

EQUAL

459

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 5082395

HSP90:HSP90 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 5082403

UniProt:Q15185 PTGES3

PTGES3

P23PTGES3TEBPFUNCTION Cytosolic prostaglandin synthase that catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) (PubMed:10922363). Molecular chaperone that localizes to genomic response elements in a hormone-dependent manner and disrupts receptor-mediated transcriptional activation, by promoting disassembly of transcriptional regulatory complexes (PubMed:11274138, PubMed:12077419). Facilitates HIF alpha proteins hydroxylation via interaction with EGLN1/PHD2, leading to recruit EGLN1/PHD2 to the HSP90 pathway (PubMed:24711448).PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Binds to the progesterone receptor (PubMed:8114727). Interacts with TERT; the interaction, together with HSP90AA1, is required for correct assembly and stabilization of the telomerase holoenzyme complex (PubMed:11274138). Interacts (via PXLE motif) with EGLN1/PHD2, recruiting EGLN1/PHD2 to the HSP90 pathway to facilitate HIF alpha proteins hydroxylation (PubMed:24711448). Interacts with HSP90AA1, FLCN, FNIP1 and FNIP2 (PubMed:27353360).DOMAIN The PXLE motif mediates interaction with EGLN1/PHD2.SIMILARITY Belongs to the p23/wos2 family.

UniProtQ15185

EQUAL

160

EQUAL

Reactome Database ID Release 755324622Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5324622ReactomeR-HSA-5324622

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5324622.1

Reactome DB_ID: 4793790

Reactome DB_ID: 5324619

HSF1 trimer:HSP90:FKBP4:PTGES3 [nucleoplasm]

HSF1 trimer:HSP90:FKBP4:PTGES3

Reactome DB_ID: 5324621

EQUAL

459

EQUAL

Reactome DB_ID: 4793790

Converted from EntitySet in Reactome

Reactome DB_ID: 5082395

Reactome DB_ID: 5082403

EQUAL

160

EQUAL

Reactome Database ID Release 755324619Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5324619ReactomeR-HSA-5324619

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5324619.1Reactome Database ID Release 755324617Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5324617ReactomeR-HSA-5324617

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5324617.111583998Pubmed2001Evidence for a mechanism of repression of heat shock factor 1 transcriptional activity by a multichaperone complexGuo, YGuettouche, TFenna, MBoellmann, FPratt, W BToft, D OSmith, David FVoellmy, RJ. Biol. Chem. 276:45791-99222609Pubmed1996A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptorNair, S CToran, E JRimerman, R AHjermstad, SSmithgall, T ESmith, David FCell Stress Chaperones 1:237-50

Reactome Database ID Release 753371568Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3371568ReactomeR-HSA-3371568

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371568.118657505Pubmed2008CoREST represses the heat shock response mediated by HSF1Gómez, Andrea VGalleguillos, DannyMaass, Juan CristóbalBattaglioli, ElenaKukuljan, ManuelAndrés, María EstelaMol. Cell 31:222-311936996Pubmed1991Attenuation of the heat shock response in HeLa cells is mediated by the release of bound heat shock transcription factor and is modulated by changes in growth and in heat shock temperaturesAbravaya, KPhillips, BMorimoto, R IGenes Dev. 5:2117-27

Reactome Database ID Release 753371571Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3371571ReactomeR-HSA-3371571

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3371571.19606196Pubmed1998Transcriptional activation domains stimulate initiation and elongation at different times and via different residuesBrown, S AWeirich, C SNewton, E MKingston, R EEMBO J. 17:3146-549121459Pubmed1997Repression of the heat shock factor 1 transcriptional activation domain is modulated by constitutive phosphorylationKline, M PMorimoto, R IMol. Cell. Biol. 17:2107-159011567Pubmed1997Heat shock factor-1 protein in heat shock factor-1 gene-transfected human epidermoid A431 cells requires phosphorylation before inducing heat shock protein-70 productionDing, X ZTsokos, G CKiang, J GJ. Clin. Invest. 99:136-438631933Pubmed1996Activation of heat shock factor 1 DNA binding precedes stress-induced serine phosphorylation. Evidence for a multistep pathway of regulationCotto, J JKline, MMorimoto, R IJ. Biol. Chem. 271:3355-8GO1900034

GO biological process