BioPAX pathway converted from "AKT phosphorylates targets in the nucleus" in the Reactome database. AKT phosphorylates targets in the nucleus AKT phosphorylates targets in the nucleus After translocation into the nucleus, AKT can phosphorylate a number of targets there such as CREB, forkhead transcription factors, SRK and NUR77. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 2.7.11.1 AKT phosphorylates CREB1 AKT phosphorylates CREB1 AKT phosphorylates CREB (cAMP response element-binding protein) at serine 133 and activates gene expression via a CREB-dependent mechanism, thus promoting cell survival. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 52777 1 nucleoplasm GO 0005654 UniProt:P16220 CREB1 CREB1 CREB1 FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (PubMed:15964553). Forms a complex with KMT2A and CREBBP (PubMed:23651431, PubMed:14506290, PubMed:14536081, PubMed:15454081, PubMed:15733869, PubMed:15964553, PubMed:16325578, PubMed:16908542, PubMed:20573984, PubMed:21172805) (By similarity). Interacts with TOX4; CREB1 is required for full induction of TOX4-dependent activity and the interaction is increased by cAMP and inhibited by insulin (By similarity).SUBUNIT (Microbial infection) Interacts with hepatitis B virus/HBV protein X.SUBUNIT (Microbial infection) Interacts with HTLV-1 protein Tax.PTM Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119 (PubMed:15964553).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.DISEASE A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.SIMILARITY Belongs to the bZIP family. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt P16220 Chain Coordinates 1 EQUAL 341 EQUAL Reactome DB_ID: 29358 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 111910 1 O-phospho-L-serine at 133 133 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 p-T,p-S-AKT [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-T308,S473-AKT1 [nucleoplasm] UniProt P31749 GO 0004674 GO molecular function Reactome Database ID Release 82 199274 Database 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=199274 Reactome Database ID Release 82 199298 Database 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=199298 Reactome R-HSA-199298 2 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-199298.2 9829964 Pubmed 1998 CREB is a regulatory target for the protein kinase Akt/PKB Du, K Montminy, M J Biol Chem 273:32377-9 GO 0043491 GO biological process 2.7.11.1 AKT phosphorylates FOXO transcription factors AKT phosphorylates FOXO transcription factors AKT-mediated phosphorylation of Forkhead box (FOX) transcription factors of the FOXO family, FOXO1 (FKHR), FOXO3 (FoxO3a, also known as FKHRL1) and FOXO4 (AFX) contributes to PI3K/AKT signaling-stimulated cell survival and growth. Activated AKT1 phosphorylates FOXO1 on threonine residue T24 and serine residues S256 and S319 (Rena et al. 1999), FOXO3 on threonine residue T32 and serine residues S253 and S315 (Brunet et al. 1999), and FOXO4 on threonine residue T32 and serine residues S197 and S262 (Kops et al. 1999).<br>Based on studies with recombinant mouse Foxo6 expressed in the human embryonic kidney cell line HEK293, FOXO6 has two conserved AKT phosphorylation sites: T26 and S184. Mouse Foxo6 has a third predicted Akt phosphorylation site at the C-terminus, T338, which is not present in other Foxo family members and is not conserved in human FOXO6. T26 and S184 are phosphorylated in response to growth factors known to activate PI3K/AKT signaling, but AKT has not been explicitly identified as the responsible kinase. In contrast to other FOXO family members, FOXO6 remains predominantly nuclear irrespective of growth factor-induced signaling, and only a small portion of phosphorylated FOXO6 may shuttle to the cytosol. Phosphorylation of FOXO6 on putative AKT sites, however, may inhibit binding of FOXO6 to target DNA sites (Jacobs et al. 2003, van der Heide et al. 2005).<br>Protein phosphatase DUSP6 (MKP3) may act to dephosphorylate FOXO1 after AKT-mediated phosphorylation (Rodrigues et al. 2017). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Donlon, Timothy, 2018-10-17 Reviewed: Bertaggia, Enrico, 2018-10-26 Edited: Orlic-Milacic, Marija, 2018-10-31 Converted from EntitySet in Reactome Reactome DB_ID: 199272 1 FOXO1,FOXO3,FOXO4,(FOXO6) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity FOXO1 [nucleoplasm] FOXO3 [nucleoplasm] FOXO4 [nucleoplasm] UniProt Q12778 UniProt O43524 UniProt P98177 Reactome DB_ID: 29358 3 Reactome DB_ID: 113582 3 Converted from EntitySet in Reactome Reactome DB_ID: 9614997 1 p-T24,S256,S319-FOXO1,p-T32,S253,S315-FOXO3,p-T32,S197,S262-FOXO4,(p-T26,S184-FOXO6) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-T32,S197,S262-FOXO4 [nucleoplasm] p-T24,S256,S319-FOXO1 [nucleoplasm] p-T32,S253,S315-FOXO3 [nucleoplasm] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 82 199299 Database 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=199299 Reactome R-HSA-199299 4 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-199299.4 10358075 Pubmed 1999 Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B Rena, G Guo, S Cichy, SC Unterman, TG Cohen, P J Biol Chem 274:17179-83 12857750 Pubmed 2003 FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics Jacobs, Frank M J van der Heide, Lars P Wijchers, Patrick J E C Burbach, J Peter H Hoekman, Marco F M Smidt, Marten P J. Biol. Chem. 278:35959-67 10102273 Pubmed 1999 Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor Brunet, A Bonni, A Zigmond, MJ Lin, MZ Juo, P Hu, LS Anderson, MJ Arden, KC Blenis, J Greenberg, ME Cell 96:857-68 15987244 Pubmed 2005 FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling van der Heide, Lars P Jacobs, Frank M J Burbach, J Peter H Hoekman, Marco F M Smidt, Marten P Biochem. J. 391:623-9 28866049 Pubmed 2017 Overexpression of Mitogen-activated protein kinase phosphatase-3 (MKP-3) reduces FoxO1 phosphorylation in mice hypothalamus Rodrigues, Bárbara de Almeida Kuga, Gabriel Keine Muñoz, Vitor Rosetto Gaspar, Rafael Calais Tavares, Mariana Rosolen Botezelli, José Diego da Silva, Adelino Sanchez Ramos Cintra, Dennys Esper de Moura, Leandro Pereira Simabuco, Fernando Moreira Ropelle, Eduardo Rochete Pauli, José Rodrigo Neurosci. Lett. 659:14-17 2.7.11.1 AKT can phosphorylate RSK AKT can phosphorylate RSK Ribosomal protein S6 kinase beta-2 (RSK) activation is a highly conserved mitogenic response, and the activities of RSK are stimulated by multiple serine/threonine phosphorylations by different upstream kinases, one of which is AKT. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 199877 1 UniProt:Q9UBS0 RPS6KB2 RPS6KB2 STK14B RPS6KB2 FUNCTION Phosphorylates specifically ribosomal protein S6 (PubMed:29750193). Seems to act downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression in an alternative pathway regulated by MEAK7 (PubMed:29750193).PTM Phosphorylated and activated by MTOR. Phosphorylation by PKC within the NLS in response to mitogenic stimuli causes cytoplasmic retention.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily. UniProt Q9UBS0 1 EQUAL 482 EQUAL Reactome DB_ID: 29358 2 Reactome DB_ID: 113582 2 Reactome DB_ID: 199844 1 O-phospho-L-serine at 15 15 EQUAL O-phospho-L-serine at 356 356 EQUAL 1 EQUAL 482 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 82 199839 Database 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=199839 Reactome R-HSA-199839 2 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-199839.2 10490848 Pubmed 1999 Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt Koh, H Jee, K Lee, B Kim, J Kim, D Yun, YH Kim, JW Choi, HS Chung, J Oncogene 18:5115-9 2.7.11.1 AKT can phosphorylate NR4A1 (NUR77) AKT can phosphorylate NR4A1 (NUR77) AKT inhibits DNA binding of NUR77 and inhibits its pro-apoptotic function (PMID 11438550). However, the relevance of AKT for NUR77 phosphorylation has recently been questioned: according to recent work, NUR77 is phosphorylated by RSK (and MSK) rather than by AKT (PMID 16223362). Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 29358 1 Reactome DB_ID: 199831 1 UniProt:P22736 NR4A1 NR4A1 NR4A1 HMR GFRP1 NAK1 FUNCTION Orphan nuclear receptor. May act concomitantly with NURR1 in regulating the expression of delayed-early genes during liver regeneration. Binds the NGFI-B response element (NBRE) 5'-AAAAGGTCA-3' (By similarity). May inhibit NF-kappa-B transactivation of IL2. Participates in energy homeostasis by sequestrating the kinase STK11 in the nucleus, thereby attenuating cytoplasmic AMPK activation. Plays a role in the vascular response to injury (By similarity).SUBUNIT Binds DNA as a monomer (By similarity). Interacts with GADD45GIP1 (PubMed:15459248). Interacts with STK11 (PubMed:22983157). Interacts with IFI27 (PubMed:22427340). Heterodimer (via DNA-binding domain) with RXRA (via C-terminus); DNA-binding of the heterodimer is enhanced by 9-cis retinoic acid (PubMed:17761950, PubMed:15509776). Competes for the RXRA interaction with EP300 and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950).TISSUE SPECIFICITY Fetal muscle and adult liver, brain and thyroid.INDUCTION By growth-stimulating agents.PTM Phosphorylated at Ser-351 by RPS6KA1 and RPS6KA3 in response to mitogenic or stress stimuli.PTM Acetylated by p300/CBP, acetylation increases stability. Deacetylated by HDAC1.SIMILARITY Belongs to the nuclear hormone receptor family. NR4 subfamily. UniProt P22736 1 EQUAL 598 EQUAL Reactome DB_ID: 113582 1 Reactome DB_ID: 199846 1 O-phospho-L-serine at 351 351 EQUAL 1 EQUAL 598 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 202072 Reactome Database ID Release 82 199863 Database 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=199863 Reactome R-HSA-199863 2 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-199863.2 11274386 Pubmed 2001 Akt phosphorylates and regulates the orphan nuclear receptor Nur77 Pekarsky, Y Hallas, C Palamarchuk, A Koval, A Bullrich, F Hirata, Y Bichi, R Letofsky, J Croce, CM Proc Natl Acad Sci U S A 98:3690-4 Reactome Database ID Release 82 198693 Database 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=198693 Reactome R-HSA-198693 2 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-198693.2