BioPAX pathway converted from "Intracellular signaling by second messengers" in the Reactome database. Intracellular signaling by second messengers This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PI3K/AKT Signaling PIP3 activates AKT signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT PIP3 recruits AKT to the membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PIP3 PI(3,4,5)P3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate Phosphatidylinositol-3,4,5-trisphosphate Reactome DB_ID: 179838 plasma membrane GENE ONTOLOGY GO:0005886 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) [ChEBI:57836] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) 2,3-bis(alkanoyloxy)propyl (1S,2S,3R,4S,5S,6S)-2,6-dihydroxy-3,4,5-tris(phosphonatooxy)cyclohexyl phosphate a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) ChEBI CHEBI:57836 Reactome Database ID Release 83 179838 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=179838 Reactome R-ALL-179838 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-ALL-179838.4 Reactome http://www.reactome.org COMPOUND C05981 additional information MI MI:0361 Converted from EntitySet in Reactome AKT Reactome DB_ID: 10911915 Converted from EntitySet in Reactome Homologues of AKT1 Reactome DB_ID: 10911907 AKT1 P11792 Reactome DB_ID: 10911903 cytosol GENE ONTOLOGY GO:0005829 UniProt:P11792 Saccharomyces cerevisiae NCBI Taxonomy 4932 UniProt P11792 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10911903 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=10911903 Reactome R-SCE-58252 1 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-SCE-58252.1 AKT1 P12688 Reactome DB_ID: 10911905 UniProt:P12688 UniProt P12688 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10911905 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=10911905 Reactome R-SCE-58252-2 1 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-SCE-58252-2.1 Reactome Database ID Release 83 10911907 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=10911907 Reactome R-SCE-58252-3 1 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-SCE-58252-3.1 Converted from EntitySet in Reactome Homologues of AKT3 Reactome DB_ID: 10911913 AKT3 P11792 Reactome DB_ID: 10911909 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10911909 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=10911909 Reactome R-SCE-2976007 1 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-SCE-2976007.1 AKT3 P12688 Reactome DB_ID: 10911911 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10911911 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=10911911 Reactome R-SCE-2976007-2 1 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-SCE-2976007-2.1 Reactome Database ID Release 83 10911913 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=10911913 Reactome R-SCE-2976007-3 1 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-SCE-2976007-3.1 Converted from EntitySet in Reactome Homologues of AKT2 Reactome DB_ID: 10907842 AKT2 P11792 Reactome DB_ID: 10907835 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10907835 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=10907835 Reactome R-SCE-49859 1 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-SCE-49859.1 AKT2 P12688 Reactome DB_ID: 10907840 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10907840 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=10907840 Reactome R-SCE-49859-2 1 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-SCE-49859-2.1 Reactome Database ID Release 83 10907842 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=10907842 Reactome R-SCE-49859-3 1 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-SCE-49859-3.1 Reactome Database ID Release 83 10911915 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=10911915 Reactome R-SCE-202088 1 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-SCE-202088.1 AKT:PIP3 Reactome DB_ID: 10910069 1 Converted from EntitySet in Reactome AKT Reactome DB_ID: 10910067 Converted from EntitySet in Reactome Homologues of AKT1 Reactome DB_ID: 10910053 AKT1 P11792 Reactome DB_ID: 10910049 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910049 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=10910049 Reactome R-SCE-199416 1 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-SCE-199416.1 AKT1 P12688 Reactome DB_ID: 10910051 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910051 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=10910051 Reactome R-SCE-199416-2 1 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-SCE-199416-2.1 Reactome Database ID Release 83 10910053 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=10910053 Reactome R-SCE-199416-3 1 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-SCE-199416-3.1 Converted from EntitySet in Reactome Homologues of AKT2 Reactome DB_ID: 10910059 AKT2 P11792 Reactome DB_ID: 10910055 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10910055 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=10910055 Reactome R-SCE-202053 1 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-SCE-202053.1 AKT2 P12688 Reactome DB_ID: 10910057 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10910057 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=10910057 Reactome R-SCE-202053-2 1 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-SCE-202053-2.1 Reactome Database ID Release 83 10910059 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=10910059 Reactome R-SCE-202053-3 1 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-SCE-202053-3.1 Converted from EntitySet in Reactome Homologues of AKT3 Reactome DB_ID: 10910065 AKT3 P11792 Reactome DB_ID: 10910061 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910061 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=10910061 Reactome R-SCE-2976006 1 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-SCE-2976006.1 AKT3 P12688 Reactome DB_ID: 10910063 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910063 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=10910063 Reactome R-SCE-2976006-2 1 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-SCE-2976006-2.1 Reactome Database ID Release 83 10910065 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=10910065 Reactome R-SCE-2976006-3 1 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-SCE-2976006-3.1 Reactome Database ID Release 83 10910067 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=10910067 Reactome R-SCE-202052 1 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-SCE-202052.1 1 Reactome Database ID Release 83 10910069 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=10910069 Reactome R-SCE-2317329 1 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-SCE-2317329.1 Reactome Database ID Release 83 10916727 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=10916727 Reactome R-SCE-2317332 1 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-SCE-2317332.1 GENE ONTOLOGY GO:0032148 gene ontology term for cellular process MI MI:0359 PIP3 generated by PI3K recruits AKT (also known as protein kinase B) to the membrane, through its PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation (Scheid et al. 2002). In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied. 2008 The role of Akt3 in Platelet Activation O'Brien, K Stojanovic, A Hay, N Du, X Arteriosclerosis, Thrombosis, and Vascular Biology 28:e162 17914025 Pubmed 2008 The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation Yin, H Stojanovic, A Hay, N Du, X Blood 111:658-65 12167717 Pubmed 2002 Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B Scheid, MP Marignani, PA Woodgett, JR Mol Cell Biol 22:6247-60 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT PIP3 recruits PDPK1 to the membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PDPK1 Q12236 Reactome DB_ID: 10910682 UniProt:Q12236 UniProt Q12236 1 EQUAL 556 EQUAL Reactome Database ID Release 83 10910682 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=10910682 Reactome R-SCE-202210 1 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-SCE-202210.1 PDPK1:PIP3 Reactome DB_ID: 10907828 1 PDPK1 Q12236 Reactome DB_ID: 10907826 1 EQUAL 556 EQUAL Reactome Database ID Release 83 10907826 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=10907826 Reactome R-SCE-61459 1 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-SCE-61459.1 1 Reactome Database ID Release 83 10907828 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=10907828 Reactome R-SCE-109697 1 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-SCE-109697.1 Reactome Database ID Release 83 10916721 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=10916721 Reactome R-SCE-2316429 1 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-SCE-2316429.1 PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999). 9895304 Pubmed 1999 Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1 Currie, RA Walker, KS Gray, A Deak, M Casamayor, A Downes, CP Cohen, P Alessi, DR Lucocq, J Biochem J 337:575-83 LEFT-TO-RIGHT 2.7.11.1 TORC2 (mTOR) phosphorylates AKT at S473 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 83 113592 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=113592 Reactome R-ALL-113592 5 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-ALL-113592.5 COMPOUND C00002 p-S-AKT:PIP3 Reactome DB_ID: 10910095 1 Converted from EntitySet in Reactome p-S-AKT Reactome DB_ID: 10910093 Converted from EntitySet in Reactome Homologues of p-S473-AKT1 Reactome DB_ID: 10910077 P11792 phospho-p-S473-AKT1 Reactome DB_ID: 10910072 473 EQUAL O-phospho-L-serine MOD MOD:00046 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910072 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=10910072 Reactome R-SCE-377265 1 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-SCE-377265.1 P12688 phospho-p-S473-AKT1 Reactome DB_ID: 10910075 473 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910075 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=10910075 Reactome R-SCE-377265-2 1 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-SCE-377265-2.1 Reactome Database ID Release 83 10910077 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=10910077 Reactome R-SCE-377265-3 1 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-SCE-377265-3.1 Converted from EntitySet in Reactome Homologues of p-S474-AKT2 Reactome DB_ID: 10910083 P11792 phospho-p-S474-AKT2 Reactome DB_ID: 10910079 474 EQUAL 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10910079 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=10910079 Reactome R-SCE-2317312 1 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-SCE-2317312.1 P12688 phospho-p-S474-AKT2 Reactome DB_ID: 10910081 474 EQUAL 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10910081 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=10910081 Reactome R-SCE-2317312-2 1 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-SCE-2317312-2.1 Reactome Database ID Release 83 10910083 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=10910083 Reactome R-SCE-2317312-3 1 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-SCE-2317312-3.1 Converted from EntitySet in Reactome Homologues of p-S472-AKT3 Reactome DB_ID: 10910091 P11792 phospho-p-S472-AKT3 Reactome DB_ID: 10910086 472 EQUAL 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910086 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=10910086 Reactome R-SCE-3009363 1 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-SCE-3009363.1 P12688 phospho-p-S472-AKT3 Reactome DB_ID: 10910089 472 EQUAL 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910089 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=10910089 Reactome R-SCE-3009363-2 1 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-SCE-3009363-2.1 Reactome Database ID Release 83 10910091 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=10910091 Reactome R-SCE-3009363-3 1 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-SCE-3009363-3.1 Reactome Database ID Release 83 10910093 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=10910093 Reactome R-SCE-2317317 1 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-SCE-2317317.1 1 Reactome Database ID Release 83 10910095 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=10910095 Reactome R-SCE-2317310 1 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-SCE-2317310.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 83 29370 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=29370 Reactome R-ALL-29370 5 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-ALL-29370.5 COMPOUND C00008 ACTIVATION activeUnit: #Protein31 TORC2 complex Reactome DB_ID: 10910129 TSC11 RICTOR P40061 Reactome DB_ID: 10910100 UniProt:P40061 TSC11 UniProt P40061 1 EQUAL 1708 EQUAL Reactome Database ID Release 83 10910100 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=10910100 Reactome R-SCE-198632 1 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-SCE-198632.1 1 TOR2 MTOR P32600 Reactome DB_ID: 10910110 UniProt:P32600 TOR2 UniProt P32600 1 EQUAL 2549 EQUAL Reactome Database ID Release 83 10910110 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=10910110 Reactome R-SCE-165662 1 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-SCE-165662.1 1 AVO1 MAPKAP1 Q08236 Reactome DB_ID: 10910115 UniProt:Q08236 AVO1 UniProt Q08236 2 EQUAL 522 EQUAL Reactome Database ID Release 83 10910115 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=10910115 Reactome R-SCE-3006620 1 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-SCE-3006620.1 1 Converted from EntitySet in Reactome Homologues of PRR5 Reactome DB_ID: 10910127 BIT2 PRR5 P38346 Reactome DB_ID: 10910120 UniProt:P38346 BIT2 UniProt P38346 1 EQUAL 388 EQUAL Reactome Database ID Release 83 10910120 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=10910120 Reactome R-SCE-6795323 1 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-SCE-6795323.1 PRR5 BIT61 P47041 Reactome DB_ID: 10910125 UniProt:P47041 BIT61 UniProt P47041 1 EQUAL 388 EQUAL Reactome Database ID Release 83 10910125 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=10910125 Reactome R-SCE-6795323-2 1 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-SCE-6795323-2.1 Reactome Database ID Release 83 10910127 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=10910127 Reactome R-SCE-6795323-3 1 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-SCE-6795323-3.1 1 LST8 MLST8 P41318 Reactome DB_ID: 10910105 UniProt:P41318 LST8 UniProt P41318 1 EQUAL 326 EQUAL Reactome Database ID Release 83 10910105 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=10910105 Reactome R-SCE-165676 1 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-SCE-165676.1 1 Reactome Database ID Release 83 10910129 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=10910129 Reactome R-SCE-198626 1 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-SCE-198626.1 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 83 10910130 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=10910130 Reactome Database ID Release 83 10910132 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=10910132 Reactome R-SCE-198640 1 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-SCE-198640.1 Under conditions of growth and mitogen stimulation S473 phosphorylation of AKT is carried out by mTOR (mammalian Target of Rapamycin). This kinase is found in two structurally and functionally distinct protein complexes, named TOR complex 1 (TORC1) and TOR complex 2 (TORC2). It is TORC2 complex, which is composed of mTOR, RICTOR, SIN1 (also named MAPKAP1) and LST8, that phosphorylates AKT at S473 (Sarbassov et al., 2005). This complex also regulates actin cytoskeletal reorganization (Jacinto et al., 2004; Sarbassov et al., 2004). TORC1, on the other hand, is a major regulator of ribosomal biogenesis and protein synthesis (Hay and Sonenberg, 2004). TORC1 regulates these processes largely by the phosphorylation/inactivation of the repressors of mRNA translation 4E binding proteins (4E BPs) and by the phosphorylation/activation of ribosomal S6 kinase (S6K1). TORC1 is also the principal regulator of autophagy. In other physiological conditions, other kinases may be responsible for AKT S473 phosphorylation.<br> Phosphorylation of AKT on S473 by TORC2 complex is a prerequisite for AKT phosphorylation on T308 by PDPK1 (Scheid et al. 2002, Sarabassov et al. 2005). 15314020 Pubmed 2004 Upstream and downstream of mTOR Hay, N Sonenberg, Nahum Genes Dev 18:1926-45 19303758 Pubmed 2009 PIKKing on PKB: regulation of PKB activity by phosphorylation Bozulic, L Hemmings, BA Curr Opin Cell Biol 21:256-61 15718470 Pubmed 2005 Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex Sarbassov, DD Guertin, DA Ali, SM Sabatini, DM Science 307:1098-101 15268862 Pubmed 2004 Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton Sarbassov, DD Ali, SM Kim, DH Guertin, DA Latek, RR Erdjument-Bromage, H Tempst, P Sabatini, DM Curr Biol 14:1296-302 15467718 Pubmed 2004 Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive Jacinto, E Loewith, R Schmidt, A Lin, S Ruegg, MA Hall, A Hall, MN Nat Cell Biol 6:1122-8 LEFT-TO-RIGHT AKT binds PDPK1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> p-S-AKT:PDPK1:PIP3 Reactome DB_ID: 10916723 1 1 Reactome Database ID Release 83 10916723 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=10916723 Reactome R-SCE-2317313 1 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-SCE-2317313.1 Reactome Database ID Release 83 10916725 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=10916725 Reactome R-SCE-2317314 1 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-SCE-2317314.1 Once phosphorylated on serine residue S473, AKT bound to PIP3 forms a complex with PIP3-bound PDPK1 i.e. PDK1 (Scheid et al. 2002, Sarabassov et al. 2005) AKT phosphorylates targets in the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11.1 AKT phosphorylates MKRN1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEE1 MKRN1 Q02799 Reactome DB_ID: 10914722 UniProt:Q02799 LEE1 UniProt Q02799 1 EQUAL 482 EQUAL Reactome Database ID Release 83 10914722 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=10914722 Reactome R-SCE-976042 1 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-SCE-976042.1 Q02799 phospho-LEE1 p-S109-MKRN1 Reactome DB_ID: 10927013 109 EQUAL 1 EQUAL 482 EQUAL Reactome Database ID Release 83 10927013 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=10927013 Reactome R-SCE-8948758 1 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-SCE-8948758.1 ACTIVATION activeUnit: #PhysicalEntity4 Converted from EntitySet in Reactome Active AKT p-T,p-S-AKT Reactome DB_ID: 10910254 Converted from EntitySet in Reactome Homologues of p-T308,S473-AKT1 Reactome DB_ID: 10910244 P11792 phospho-p-T308,S473-AKT1 Reactome DB_ID: 10910239 308 EQUAL O-phospho-L-threonine MOD MOD:00047 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910239 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=10910239 Reactome R-SCE-198356 1 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-SCE-198356.1 P12688 phospho-p-T308,S473-AKT1 Reactome DB_ID: 10910242 308 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910242 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=10910242 Reactome R-SCE-198356-2 1 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-SCE-198356-2.1 Reactome Database ID Release 83 10910244 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=10910244 Reactome R-SCE-198356-3 1 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-SCE-198356-3.1 Converted from EntitySet in Reactome Homologues of p-T309,S474-AKT2 Reactome DB_ID: 10907854 P11792 phospho-p-T309,S474-AKT2 Reactome DB_ID: 10907848 309 EQUAL 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10907848 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=10907848 Reactome R-SCE-202062 1 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-SCE-202062.1 P12688 phospho-p-T309,S474-AKT2 Reactome DB_ID: 10907852 309 EQUAL 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10907852 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=10907852 Reactome R-SCE-202062-2 1 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-SCE-202062-2.1 Reactome Database ID Release 83 10907854 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=10907854 Reactome R-SCE-202062-3 1 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-SCE-202062-3.1 Converted from EntitySet in Reactome Homologues of p-T305,S472-AKT3 Reactome DB_ID: 10910252 P11792 phospho-p-T305,S472-AKT3 Reactome DB_ID: 10910247 305 EQUAL 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910247 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=10910247 Reactome R-SCE-3009367 1 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-SCE-3009367.1 P12688 phospho-p-T305,S472-AKT3 Reactome DB_ID: 10910250 305 EQUAL 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910250 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=10910250 Reactome R-SCE-3009367-2 1 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-SCE-3009367-2.1 Reactome Database ID Release 83 10910252 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=10910252 Reactome R-SCE-3009367-3 1 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-SCE-3009367-3.1 Reactome Database ID Release 83 10910254 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=10910254 Reactome R-SCE-202074 1 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-SCE-202074.1 Reactome Database ID Release 83 10911827 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=10911827 Reactome Database ID Release 83 10927015 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=10927015 Reactome R-SCE-8948757 1 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-SCE-8948757.1 GENE ONTOLOGY GO:0043491 AKT1 (and possibly AKT2 and AKT3), activated in response to EGF treatment, phosphorylates MKRN1, an E3 ubiquitin ligase, on serine residue S109. AKT-mediated phosphorylation results in stabilization of MKRN1, protecting it from ubiquitination and proteasome-mediated degradation (Lee et al. 2015). 26183061 Pubmed 2015 PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis Lee, Min-Sik Jeong, Man-Hyung Lee, Hyun-Woo Han, Hyun-Ji Ko, Aram Hewitt, SM Kim, Jae-Hoon Chun, Kyung-Hee Chung, Joon-Yong Lee, Cheolju Cho, Hanbyoul Song, Jaewhan Nat Commun 6:7769 Reactome Database ID Release 83 10930653 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=10930653 Reactome R-SCE-198323 1 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-SCE-198323.1 Following activation, AKT can phosphorylate an array of target proteins in the cytoplasm, many of which are involved in cell survival control. Phosphorylation of TSC2 feeds positively to the TOR kinase, which, in turn, contributes to AKT activation (positive feedback loop). AKT phosphorylates targets in the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11.1 AKT can phosphorylate RSK This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> P38070 RPS6KB2 Reactome DB_ID: 10910286 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:P38070 UniProt P38070 1 EQUAL 482 EQUAL Reactome Database ID Release 83 10910286 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=10910286 Reactome R-SCE-199877 1 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-SCE-199877.1 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 Reactome Database ID Release 83 29358 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=29358 Reactome R-ALL-29358 3 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-ALL-29358.3 COMPOUND C00002 2 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 Reactome Database ID Release 83 113582 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=113582 Reactome R-ALL-113582 3 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-ALL-113582.3 COMPOUND C00008 2 P38070 phospho-p-S15,S356-RPS6KB2 Reactome DB_ID: 10910290 15 EQUAL 356 EQUAL 1 EQUAL 482 EQUAL Reactome Database ID Release 83 10910290 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=10910290 Reactome R-SCE-199844 1 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-SCE-199844.1 ACTIVATION Converted from EntitySet in Reactome Active AKT p-T,p-S-AKT p-T308,S473-AKT1,(p-T309,S474-AKT2,p-T305,S472-AKT3) Reactome DB_ID: 10910310 Converted from EntitySet in Reactome Homologues of p-T308,S473-AKT1 Reactome DB_ID: 10910296 P11792 phospho-p-T308,S473-AKT1 Reactome DB_ID: 10910292 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910292 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=10910292 Reactome R-SCE-198357 1 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-SCE-198357.1 P12688 phospho-p-T308,S473-AKT1 Reactome DB_ID: 10910294 1 EQUAL 480 EQUAL Reactome Database ID Release 83 10910294 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=10910294 Reactome R-SCE-198357-2 1 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-SCE-198357-2.1 Reactome Database ID Release 83 10910296 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=10910296 Reactome R-SCE-198357-3 1 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-SCE-198357-3.1 Converted from EntitySet in Reactome Homologues of p-T309,S474-AKT2 Reactome DB_ID: 10910302 P11792 phospho-p-T309,S474-AKT2 Reactome DB_ID: 10910298 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10910298 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=10910298 Reactome R-SCE-202087 1 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-SCE-202087.1 P12688 phospho-p-T309,S474-AKT2 Reactome DB_ID: 10910300 1 EQUAL 481 EQUAL Reactome Database ID Release 83 10910300 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=10910300 Reactome R-SCE-202087-2 1 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-SCE-202087-2.1 Reactome Database ID Release 83 10910302 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=10910302 Reactome R-SCE-202087-3 1 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-SCE-202087-3.1 Converted from EntitySet in Reactome Homologues of p-T305,S472-AKT3 Reactome DB_ID: 10910308 P11792 phospho-p-T305,S472-AKT3 Reactome DB_ID: 10910304 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910304 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=10910304 Reactome R-SCE-3009365 1 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-SCE-3009365.1 P12688 phospho-p-T305,S472-AKT3 Reactome DB_ID: 10910306 1 EQUAL 479 EQUAL Reactome Database ID Release 83 10910306 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=10910306 Reactome R-SCE-3009365-2 1 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-SCE-3009365-2.1 Reactome Database ID Release 83 10910308 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=10910308 Reactome R-SCE-3009365-3 1 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-SCE-3009365-3.1 Reactome Database ID Release 83 10910310 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=10910310 Reactome R-SCE-202072 1 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-SCE-202072.1 Reactome Database ID Release 83 10910311 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=10910311 Reactome Database ID Release 83 10910313 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=10910313 Reactome R-SCE-199839 1 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-SCE-199839.1 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. 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 Reactome Database ID Release 83 10929845 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=10929845 Reactome R-SCE-198693 1 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-SCE-198693.1 After translocation into the nucleus, AKT can phosphorylate a number of targets there such as CREB, forkhead transcription factors, SRK and NUR77. Negative regulation of the PI3K/AKT network This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 3.1.3.67 PTEN dephosphorylates PIP3 PI(3,4,5)P3 is dephosphorylated to PI (4,5)P2 by PTEN at the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 83 29356 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=29356 Reactome R-ALL-29356 5 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-ALL-29356.5 COMPOUND C00001 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 29372 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 83 29372 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=29372 Reactome R-ALL-29372 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-ALL-29372.4 COMPOUND C00009 PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) [ChEBI:58456] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate(5-) a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) 2,3-bis(alkanoyloxy)propyl (1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-bis(phosphonatooxy)cyclohexyl phosphate ChEBI CHEBI:58456 Reactome Database ID Release 83 179856 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=179856 Reactome R-ALL-179856 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-ALL-179856.4 COMPOUND C04637 ACTIVATION TEP1 PTEN P53916 Reactome DB_ID: 10910279 UniProt:P53916 TEP1 UniProt P53916 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10910279 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=10910279 Reactome R-SCE-199420 1 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-SCE-199420.1 GENE ONTOLOGY GO:0016314 Reactome Database ID Release 83 10910280 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=10910280 Reactome Database ID Release 83 10910282 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=10910282 Reactome R-SCE-199456 1 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-SCE-199456.1 GENE ONTOLOGY GO:0051898 At the plasma membrane, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase aka phosphatase and tensin homolog (PTEN) dephosphorylates phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Maehama & Dixon 1998, Myers et al. 1998, Das et al. 2003). The PI3K network is negatively regulated by phospholipid phosphatases that dephosphorylate PIP3, thus hampering AKT activation (Myers et al. 1998). The tumour suppressor PTEN is the primary phospholipid phosphatase.<br>Early studies indicated that magnesium ion, Mg2+, was needed for the catalytic activity of PTEN isolated from bovine thymus (Kabuyama et al. 1996). Subsequent studies have shown that PTEN was catalytically active in buffers free of magnesium and magnesium was not detected as part of the PTEN crystal (Lee et al. 1999). 9811831 Pubmed 1998 The lipid phosphatase activity of PTEN is critical for its tumor supressor function Myers, MP Pass, I Batty, IH van der Kaay, J Stolarov, JP Hemmings, BA Downes, CP Tonks, NK Wigler, Michael H Proc Natl Acad Sci U S A 95:13513-8 12808147 Pubmed 2003 Membrane-binding and activation mechanism of PTEN Das, S Dixon, JE Cho, W Proc Natl Acad Sci U S A 100:7491-6 10555148 Pubmed 1999 Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association Lee, Jie-Oh Yang, Haijuan Georgescu, Maria-Magdalena Di Cristofano, Antonio Maehama, Tomohiko Shi, Y Dixon, Jack Pandolfi, Pier Pavletich, Nikola Cell 99:323-34 8681945 Pubmed 1996 Purification and characterization of the phosphatidylinositol-3,4,5-trisphosphate phosphatase in bovine thymus Kabuyama, Y Nakatsu, N Homma, Y Fukui, Y Eur. J. Biochem. 238:350-6 9593664 Pubmed 1998 The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate Maehama, T Dixon, JE J Biol Chem 273:13375-8 PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.1.68 PI4P is phosphorylated to PI(4,5)P2 by PIP5K1A-C at the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PI4P Phosphatidylinositol 4-phosphate 1-phosphatidyl-1D-myo-inositol 4-phosphate 1-phosphatidyl-1D-myo-inositol 4-phosphates Reactome DB_ID: 392417 1-phosphatidyl-1D-myo-inositol 4-phosphate [ChEBI:17526] 1-phosphatidyl-1D-myo-inositol 4-phosphate ChEBI CHEBI:17526 Reactome Database ID Release 83 392417 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=392417 Reactome R-ALL-392417 3 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-ALL-392417.3 COMPOUND C01277 PubChem Substance 4496 ACTIVATION MSS4 PIP5K1A P38994 Reactome DB_ID: 10915859 UniProt:P38994 MSS4 UniProt P38994 1 EQUAL 562 EQUAL Reactome Database ID Release 83 10915859 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=10915859 Reactome R-SCE-1806260 1 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-SCE-1806260.1 GENE ONTOLOGY GO:0016308 Reactome Database ID Release 83 10916003 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=10916003 Reactome Database ID Release 83 10916005 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=10916005 Reactome R-SCE-1676082 1 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-SCE-1676082.1 At the plasma membrane, phosphatidylinositol-4-phosphate 5-kinase type-1 alpha (PIP5K1A), beta (PIP5K1B), and gamma (PIP5K1C) phosphorylate phosphatidylinositol 4-phosphate (PI4P) to produce phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP5K1A (Halstead et al. 2006, Zhang et al. 1997), PIP5K1B (Zhang et al. 1997), and PIP5K1C (Di Paolo et al. 2002).<br><br>This reaction is of particular interest because its regulation by small GTPases of the RHO and ARF families, not yet annotated here, ties the process of phosphatidylinositol phosphate biosynthesis to regulation of the actin cytoskeleton and vesicular trafficking, and hence to diverse aspects of cell motility and signalling (Oude Weernink et al. 2004, 2007). 15464023 Pubmed 2004 Regulation and cellular roles of phosphoinositide 5-kinases Oude Weernink, PA Schmidt, M Jakobs, KH Eur J Pharmacol 500:87-99 16979564 Pubmed 2006 A role for PtdIns(4,5)P2 and PIP5Kalpha in regulating stress-induced apoptosis Halstead, JR van Rheenen, J Snel, MH Meeuws, S Mohammed, S D'Santos, CS Heck, AJ Jalink, K Divecha, Nullin Curr Biol 16:1850-6 12422219 Pubmed 2002 Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin Di Paolo, G Pellegrini, L Letinic, K Cestra, G Zoncu, R Voronov, S Chang, S Guo, J Wenk, MR De Camilli, Pietro Nature 420:85-9 17245604 Pubmed 2007 Phospholipase D signaling: orchestration by PIP2 and small GTPases Oude Weernink, PA López de Jesús, M Schmidt, M Naunyn Schmiedebergs Arch Pharmacol 374:399-411 9211928 Pubmed 1997 Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules Zhang, Xiaoxuan Loijens, JC Boronenkov, IV Parker, GJ Norris, FA Chen, J Thum, O Prestwich, GD Majerus, PW Anderson, RA J Biol Chem 272:17756-61 LEFT-TO-RIGHT 2.7.1.149 PI5P is phosphorylated to PI(4,5)P2 by PIP4K2 dimers at the plasma membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PI5P 1-phosphatidyl-1D-myo-inositol 5-phosphate Reactome DB_ID: 1806240 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) [ChEBI:57795] 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) 1-phosphatidyl-1D-myo-inositol 5-phosphate trianions a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate) 2,3-bis(alkanoyloxy)propyl (1R,2R,3R,4R,5S,6R)-2,3,4,6-tetrahydroxy-5-(phosphonatooxy)cyclohexyl phosphate 1-phosphatidyl-1D-myo-inositol 5-phosphate trianion ChEBI CHEBI:57795 Reactome Database ID Release 83 1806240 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=1806240 Reactome R-ALL-1806240 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-ALL-1806240.4 ACTIVATION Converted from EntitySet in Reactome PIP4K2 dimers Reactome DB_ID: 10915886 PIP4K2A:PIP4K2A Reactome DB_ID: 10915870 MSS4 PIP4K2A P38994 Reactome DB_ID: 10915868 2 EQUAL 406 EQUAL Reactome Database ID Release 83 10915868 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=10915868 Reactome R-SCE-1604641 1 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-SCE-1604641.1 2 Reactome Database ID Release 83 10915870 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=10915870 Reactome R-SCE-1806252 1 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-SCE-1806252.1 PIP4K2A:PIP4K2B Reactome DB_ID: 10915874 1 MSS4 PIP4K2B P38994 Reactome DB_ID: 10915872 1 EQUAL 416 EQUAL Reactome Database ID Release 83 10915872 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=10915872 Reactome R-SCE-1806208 1 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-SCE-1806208.1 1 Reactome Database ID Release 83 10915874 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=10915874 Reactome R-SCE-1806183 1 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-SCE-1806183.1 PIP4K2B:PIP4K2B Reactome DB_ID: 10915876 2 Reactome Database ID Release 83 10915876 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=10915876 Reactome R-SCE-1806168 1 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-SCE-1806168.1 PIP4K2A:PIP4K2C Reactome DB_ID: 10915880 MSS4 PIP4K2C P38994 Reactome DB_ID: 10915878 2 EQUAL 421 EQUAL Reactome Database ID Release 83 10915878 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=10915878 Reactome R-SCE-1604638 1 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-SCE-1604638.1 1 1 Reactome Database ID Release 83 10915880 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=10915880 Reactome R-SCE-6808605 1 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-SCE-6808605.1 PIP4K2C:PIP4K2C Reactome DB_ID: 10915882 2 Reactome Database ID Release 83 10915882 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=10915882 Reactome R-SCE-6808604 1 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-SCE-6808604.1 PIP4K2B:PIP4K2C Reactome DB_ID: 10915884 1 1 Reactome Database ID Release 83 10915884 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=10915884 Reactome R-SCE-6808599 1 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-SCE-6808599.1 Reactome Database ID Release 83 10915886 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=10915886 Reactome R-SCE-1806229 1 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-SCE-1806229.1 GENE ONTOLOGY GO:0016309 Reactome Database ID Release 83 10915887 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=10915887 Reactome Database ID Release 83 10915889 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=10915889 Reactome R-SCE-1675776 1 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-SCE-1675776.1 At the plasma membrane, phosphatidylinositol-5-phosphate 4-kinase type-2 alpha (PIP4K2A), beta (PIP4K2B) and gamma (PIP4K2C) homodimers and heterodimers (Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015) phosphorylate phosphatidylinositol 5-phosphate (PI5P) to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2).<br><br>The following lists the above proteins with their corresponding literature references: PIP4K2A (Rameh et al. 1997, Clarke et al. 2008, Clarke and Irvine 2013), PIP4K2B (Rameh et al. 1997, Clarke and Irvine 2013) and PIP4K2C (Clarke and Irvine 2013, Clarke et al. 2015). 18753295 Pubmed 2008 Localization of phosphatidylinositol phosphate kinase IIgamma in kidney to a membrane trafficking compartment within specialized cells of the nephron Clarke, JH Emson, PC Irvine, RF Am J Physiol Renal Physiol 295:F1422-30 19896968 Pubmed 2010 Localization, regulation and function of type II phosphatidylinositol 5-phosphate 4-kinases Clarke, JH Wang, M Irvine, RF Adv Enzyme Regul 50:12-8 25495341 Pubmed 2015 The function of phosphatidylinositol 5-phosphate 4-kinase γ (PI5P4Kγ) explored using a specific inhibitor that targets the PI5P-binding site Clarke, Jonathan H Giudici, Maria-Luisa Burke, John E Williams, RL Maloney, David J Marugan, Juan Irvine, Robin F Biochem. J. 466:359-67 23758345 Pubmed 2013 Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization Clarke, Jonathan H Irvine, Robin F Biochem. J. 454:49-57 9367159 Pubmed 1997 A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate Rameh, Lucia Tolias, KF Duckworth, BC Cantley, Lewis C Nature 390:192-6 LEFT-TO-RIGHT 3.1.3.16 AKT1 dephosphorylation by PP2A-B56-beta,gamma This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 2 ACTIVATION PP2A-B56-beta,gamma Reactome DB_ID: 10925134 Converted from EntitySet in Reactome PP2A-catalytic subunit C Reactome DB_ID: 10911767 PPP2CA P23594 Reactome DB_ID: 10911765 UniProt:P23594 UniProt P23594 1 EQUAL 309 EQUAL Reactome Database ID Release 83 10911765 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=10911765 Reactome R-SCE-165971 1 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-SCE-165971.1 Reactome Database ID Release 83 10911767 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=10911767 Reactome R-SCE-165977 1 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-SCE-165977.1 1 RTS1 PPP2R5B P38903 Reactome DB_ID: 10911749 UniProt:P38903 RTS1 UniProt P38903 1 EQUAL 497 EQUAL Reactome Database ID Release 83 10911749 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=10911749 Reactome R-SCE-535469 1 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-SCE-535469.1 1 Converted from EntitySet in Reactome PP2A-subunit A Reactome DB_ID: 10911763 TPD3 PPP2R1A P31383 Reactome DB_ID: 10911759 UniProt:P31383 TPD3 UniProt P31383 2 EQUAL 589 EQUAL Reactome Database ID Release 83 10911759 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=10911759 Reactome R-SCE-165982 1 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-SCE-165982.1 Reactome Database ID Release 83 10911763 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=10911763 Reactome R-SCE-165990 1 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-SCE-165990.1 1 Reactome Database ID Release 83 10925134 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=10925134 Reactome R-SCE-6811526 1 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-SCE-6811526.1 GENE ONTOLOGY GO:0004722 Reactome Database ID Release 83 10925137 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=10925137 Reactome Database ID Release 83 10925139 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=10925139 Reactome R-SCE-6811504 1 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-SCE-6811504.1 The protein phosphatase 2A (PP2A) complex containing a regulatory subunit B56 beta (PPP2R5B) or B56 gamma (PPP2R5C) dephosphorylates activated AKT1 on threonine residue T308 and serine residue S473, thus halting PI3K/AKT signaling (Rocher et al. 2007). Phosphatidylinositol-5-phosphate (PI5P) negatively regulates PP2A-mediated dephosphorylation of AKT1 by promoting, through an unknown mechanism, an inhibitory phosphorylation on tyrosine residue Y307 (Chen et al. 1992) of the catalytic subunit of PP2A (Ramel et al. 2009). 17200115 Pubmed 2007 Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity Rocher, Géraldine Letourneux, Claire Lenormand, Philippe Porteu, Françoise J. Biol. Chem. 282:5468-77 1325671 Pubmed 1992 Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation Chen, J Martin, B L Brautigan, D L Science 257:1261-4 19576174 Pubmed 2009 PtdIns5P protects Akt from dephosphorylation through PP2A inhibition Ramel, Damien Lagarrigue, Frédéric Dupuis-Coronas, Sophie Chicanne, Gaëtan Leslie, Nicholas Gaits-Iacovoni, Frédérique Payrastre, Bernard Tronchère, Hélène Biochem. Biophys. Res. Commun. 387:127-31 INHIBITION Reactome Database ID Release 83 9911680 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=9911680 Reactome Database ID Release 83 10930219 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=10930219 Reactome R-SCE-6811558 1 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-SCE-6811558.1 GENE ONTOLOGY GO:0014066 Phosphatidylinositol-5-phosphate (PI5P) may modulate PI3K/AKT signaling in several ways. PI5P is used as a substrate for production of phosphatidylinositol-4,5-bisphosphate, PI(4,5)P2 (Rameh et al. 1997, Clarke et al. 2008, Clarke et al. 2010, Clarke and Irvine 2013, Clarke et al. 2015), which serves as a substrate for activated PI3K, resulting in the production of PIP3 (Mandelker et al. 2009, Burke et al. 2011). The majority of PI(4,5)P2 in the cell, however, is produced from the phosphatidylinositol-4-phosphate (PI4P) substrate (Zhang et al. 1997, Di Paolo et al. 2002, Oude Weernink et al. 2004, Halstead et al. 2006, Oude Weernink et al. 2007). PIP3 is necessary for the activating phosphorylation of AKT. AKT1 can be deactivated by the protein phosphatase 2A (PP2A) complex that contains a regulatory subunit B56-beta (PPP2R5B) or B56-gamma (PPP2R5C). PI5P inhibits AKT1 dephosphorylation by PP2A through an unknown mechanism (Ramel et al. 2009). Increased PI5P levels correlate with inhibitory phosphorylation(s) of the PP2A complex. MAPK1 (ERK2) and MAPK3 (ERK1) are involved in inhibitory phosphorylation of PP2A, in a process that involves IER3 (IEX-1) (Letourneux et al. 2006, Rocher et al. 2007). It is uncertain, however, whether PI5P is in any way involved in ERK-mediated phosphorylation of PP2A or if it regulates another PP2A kinase. 16456541 Pubmed 2006 B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK Letourneux, C Rocher, G Porteu, F EMBO J 25:727-38 19805105 Pubmed 2009 A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane Mandelker, Diana Gabelli, Sandra B Schmidt-Kittler, Oleg Zhu, Jiuxiang Cheong, Ian Huang, Chuan-Hsiang Kinzler, KW Vogelstein, B Amzel, L Mario Proc. Natl. Acad. Sci. U.S.A. 106:16996-7001 21827948 Pubmed 2011 Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110? Burke, John E Vadas, Oscar Berndt, Alex Finegan, Tara Perisic, O Williams, RL Structure 19:1127-37 Reactome Database ID Release 83 10929835 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=10929835 Reactome R-SCE-199418 1 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-SCE-199418.1 The PI3K/AKT network is negatively regulated by phosphatases that dephosphorylate PIP3, thus hampering AKT activation. LEFT-TO-RIGHT PDPK1 binds PIP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PDPK1:PIP2 Reactome DB_ID: 10916717 1 1 Reactome Database ID Release 83 10916717 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=10916717 Reactome R-SCE-2219520 1 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-SCE-2219520.1 Reactome Database ID Release 83 10916719 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=10916719 Reactome R-SCE-2219524 1 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-SCE-2219524.1 PDPK1 (PDK1) possesses low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane, in the absence of PI3K activity (Currie et al. 1999). PTEN Regulation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Regulation of PTEN gene transcription This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT MAF1 translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> MAF1 MAF1 P41910 Reactome DB_ID: 10926958 UniProt:P41910 MAF1 UniProt P41910 1 EQUAL 256 EQUAL Reactome Database ID Release 83 10926958 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=10926958 Reactome R-SCE-8944460 1 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-SCE-8944460.1 MAF1 MAF1 P41910 Reactome DB_ID: 10926956 1 EQUAL 256 EQUAL Reactome Database ID Release 83 10926956 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=10926956 Reactome R-SCE-8944422 1 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-SCE-8944422.1 Reactome Database ID Release 83 10926965 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=10926965 Reactome R-SCE-8944457 1 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-SCE-8944457.1 Phosphorylation of MAF1 by the activated mTORC1 complex inhibits translocation of MAF1 to the nucleus, and hence its transcriptional activity, but the mechanism has not been elucidated (Shor et al. 2010). 20233713 Pubmed 2010 Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells Shor, Boris Wu, Jiang Shakey, Quazi Toral-Barza, Lourdes Shi, Celine Follettie, Max Yu, Ker J. Biol. Chem. 285:15380-92 Reactome Database ID Release 83 10930645 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=10930645 Reactome R-SCE-8943724 1 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-SCE-8943724.1 Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016). 18172008 Pubmed 2008 Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis Escrivà, Maria Peiró, Sandra Herranz, Nicolás Villagrasa, Patricia Dave, Natàlia Montserrat-Sentís, Bàrbara Murray, Stephen A Francí, Clara Gridley, T Virtanen, Ismo García de Herreros, Antonio Mol. Cell. Biol. 28:1528-40 26910647 Pubmed 2016 MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription Li, Yue Tsang, Chi Kwan Wang, Suihai Li, Xiao-Xing Yang, Yang Fu, Liwu Huang, Wenlin Li, Ming Wang, Hui-Yun Zheng, X F Steven Hepatology 63:1928-42 11781575 Pubmed 2001 The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling Virolle, T Adamson, Eileen D Baron, V Birle, D Mercola, D Mustelin, T de Belle, I Nat. Cell Biol. 3:1124-8 25728608 Pubmed 2015 SLUG is a direct transcriptional repressor of PTEN tumor suppressor Uygur, Berna Abramo, Katrina Leikina, Evgenia Vary, Calvin Liaw, Lucy Wu, Wen-Shu Prostate 75:907-16 17974977 Pubmed 2007 Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras Vasudevan, Krishna Murthi Burikhanov, Ravshan Goswami, Anindya Rangnekar, Vivek M Cancer Res. 67:10343-50 19884659 Pubmed 2009 The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells Song, Li-Bing Li, J Liao, Wen-Ting Feng, Yan Yu, Chun-Ping Hu, Li-Juan Kong, Qing-Li Xu, Li-Hua Zhang, Xing Liu, Wan-Li Li, Man-Zhi Zhang, L Kang, Tie-Bang Fu, Li-Wu Huang, Wen-Lin Xia, Yun-Fei Tsao, Sai Wah Li, Mengfeng Band, Vimla Band, Hamid Shi, Qing-Hua Zeng, Yi-Xin Zeng, Mu-Sheng J. Clin. Invest. 119:3626-36 18487508 Pubmed 2008 SALL4 is a key regulator of survival and apoptosis in human leukemic cells Yang, Jianchang Chai, Li Gao, Chong Fowles, Taylor C Alipio, Zaida Dang, Hien Xu, Dan Fink, Louis M Ward, David C Ma, Yupo Blood 112:805-13 19440552 Pubmed 2009 Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex Lu, J Jeong, HW Kong, N Yang, Y Carroll, J Luo, HR Silberstein, LE Yupoma, LE Chai, L PLoS One 4:e5577 16702404 Pubmed 2006 Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1 Zhang, Chun-Li Zou, Yuhua Yu, Ruth T Gage, Fred H Evans, Ronald M Genes Dev. 20:1308-20 16418168 Pubmed 2006 Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells Shen, Ying H Zhang, Lin Gan, Yehua Wang, Xinwen Wang, Jian LeMaire, Scott A Coselli, Joseph S Wang, Xing Li J. Biol. Chem. 281:7727-36 11378386 Pubmed 2001 Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN Patel, L Pass, I Coxon, P Downes, C P Smith, S A MacPhee, C H Curr. Biol. 11:764-8 11545734 Pubmed 2001 Regulation of PTEN transcription by p53 Stambolic, V MacPherson, D Sas, D Lin, Y Snow, B Jang, Y Benchimol, S Mak, T W Mol. Cell 8:317-25 21289308 Pubmed 2011 Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins Yoshimi, Akihide Goyama, Susumu Watanabe-Okochi, Naoko Yoshiki, Yumiko Nannya, Yasuhito Nitta, Eriko Arai, Shunya Sato, Tomohiko Shimabe, Munetake Nakagawa, Masahiro Imai, Yoichi Kitamura, Toshio Kurokawa, Mineo Blood 117:3617-28 Regulation of PTEN localization This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Monoubiquitinated PTEN translocates to the nucleus This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TEP1 MonoUb-K13,K289-PTEN P53916 Reactome DB_ID: 10924412 13 EQUAL ubiquitinylated lysine MOD MOD:01148 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10924412 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=10924412 Reactome R-SCE-6807247 1 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-SCE-6807247.1 TEP1 MonoUb-K13,K289-PTEN P53916 Reactome DB_ID: 10924416 13 EQUAL 289 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10924416 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=10924416 Reactome R-SCE-6807264 1 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-SCE-6807264.1 Reactome Database ID Release 83 10924418 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=10924418 Reactome R-SCE-6807105 1 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-SCE-6807105.1 Monoubiquitinated PTEN translocates to the nucleus. Lysine residues K13 and K289 of PTEN are important monoubiquitination targets and their mutation abrogates PTEN nuclear localization (Trotman et al. 2007). 17218261 Pubmed 2007 Ubiquitination regulates PTEN nuclear import and tumor suppression Trotman, Lloyd C Wang, Xinjiang Alimonti, Andrea Chen, Zhenbang Teruya-Feldstein, Julie Yang, Haijuan Pavletich, Nikola P Carver, Brett S Cordon-Cardo, Carlos Erdjument-Bromage, H Tempst, P Chi, Sung-Gil Kim, Hyo-Jong Misteli, Tom Jiang, Xuejun Pandolfi, Pier Paolo Cell 128:141-56 LEFT-TO-RIGHT Deubiquitinated PTEN translocates to the cytosol This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> TEP1 PTEN P53916 Reactome DB_ID: 10920797 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10920797 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=10920797 Reactome R-SCE-6807273 1 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-SCE-6807273.1 Reactome Database ID Release 83 10924420 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=10924420 Reactome R-SCE-6807126 1 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-SCE-6807126.1 After nuclear monoubiquitinated PTEN gets deubiquitinated by USP7 (HAUSP), it translocates to the cytosol (Song et al. 2008). 18716620 Pubmed 2008 The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network Song, MS Salmena, Leonardo Carracedo, Arkaitz Egia, Ainara Lo-Coco, F Teruya-Feldstein, Julie Pandolfi, Pier Paolo Nature 455:813-7 Reactome Database ID Release 83 10930585 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=10930585 Reactome R-SCE-8948747 1 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-SCE-8948747.1 When monoubiquitinated by E3 ubiquitin ligases XIAP and NEDD4, PTEN translocates from the cytosol to the nucleus (Trotman et al. 2007, Van Themsche et al. 2009). USP7 (HAUSP)-mediated deubiquitination of monoubiquitinated nuclear PTEN promotes relocalization of PTEN to the cytosol (Song et al. 2008). 19473982 Pubmed 2009 X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization Van Themsche, Céline Leblanc, Valérie Parent, Sophie Asselin, Eric J. Biol. Chem. 284:20462-6 Regulation of PTEN stability and activity This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11.1 Casein kinase II phosphorylates PTEN This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 5 5 P53916 phospho-TEP1 p-3S,2T-PTEN Reactome DB_ID: 10925487 370 EQUAL 380 EQUAL 382 EQUAL 383 EQUAL 385 EQUAL 2 EQUAL 403 EQUAL Reactome Database ID Release 83 10925487 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=10925487 Reactome R-SCE-8850936 1 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-SCE-8850936.1 ACTIVATION Casein kinase II Reactome DB_ID: 10917039 CKB1 CSNK2B P43639 Reactome DB_ID: 10917017 UniProt:P43639 CKB1 CKB1 YGL019W FUNCTION Regulatory subunit of casein kinase II/CK2 (By similarity). As part of the kinase complex regulates the basal catalytic activity of the alpha subunit a constitutively active serine/threonine-protein kinase that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (By similarity).SUBUNIT Tetramer composed of an alpha subunit, an alpha' subunit, one beta subunit and one beta' subunit (PubMed:12242279). Interacts with FACT subunits POB3 and SPT16 (PubMed:12242279). interacts with YTA7 (PubMed:22156209).PTM Phosphorylated by alpha subunit.MISCELLANEOUS Present with 8120 molecules/cell in log phase SD medium.SIMILARITY Belongs to the casein kinase 2 subunit beta family. UniProt P43639 2 EQUAL 215 EQUAL Reactome Database ID Release 83 10917017 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=10917017 Reactome R-SCE-201693 1 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-SCE-201693.1 2 Converted from EntitySet in Reactome CSNK2(A1:A1/A1:A2/A2:A2) CKII alpha catalytic subunit Reactome DB_ID: 10917037 CSNK2A1 dimer Reactome DB_ID: 10917023 P15790 CSNK2A1 Reactome DB_ID: 10917021 UniProt:P15790 CKA1 CKA1 YIL035C FUNCTION Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (By similarity). Phosphorylates YTA7 during S-phase to promote transcription of histones (PubMed:22156209).SUBUNIT Tetramer composed of an alpha chain, an alpha', one beta chain and one beta' chain (PubMed:12242279). Interacts with FACT subunits POB3 and SPT16 (PubMed:12242279). Interacts with YTA7 (PubMed:22156209).MISCELLANEOUS Present with 7180 molecules/cell in log phase SD medium.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CK2 subfamily. UniProt P15790 1 EQUAL 391 EQUAL Reactome Database ID Release 83 10917021 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=10917021 Reactome R-SCE-201713 1 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-SCE-201713.1 2 Reactome Database ID Release 83 10917023 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=10917023 Reactome R-SCE-5083621 1 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-SCE-5083621.1 CSNK2A2 dimer Reactome DB_ID: 10917033 Converted from EntitySet in Reactome Homologues of CSNK2A2 Reactome DB_ID: 10917031 P15790 CSNK2A2 Reactome DB_ID: 10917025 1 EQUAL 350 EQUAL Reactome Database ID Release 83 10917025 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=10917025 Reactome R-SCE-201721 1 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-SCE-201721.1 P19454 CSNK2A2 Reactome DB_ID: 10917029 UniProt:P19454 CKA2 CKA2 YOR061W YOR29-12 FUNCTION Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine (By similarity). Phosphorylates YTA7 during S-phase to promote transcription of histones (PubMed:22156209).SUBUNIT Tetramer composed of an alpha chain, an alpha', one beta chain and one beta' chain (PubMed:12242279). Interacts with FACT subunits POB3 and SPT16 (PubMed:12242279). Interacts with NAP1 (PubMed:18086883). Interacts with YTA7 (PubMed:22156209).MISCELLANEOUS Present with 4540 molecules/cell in log phase SD medium.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CK2 subfamily. UniProt P19454 1 EQUAL 350 EQUAL Reactome Database ID Release 83 10917029 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=10917029 Reactome R-SCE-201721-2 1 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-SCE-201721-2.1 Reactome Database ID Release 83 10917031 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=10917031 Reactome R-SCE-201721-3 1 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-SCE-201721-3.1 2 Reactome Database ID Release 83 10917033 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=10917033 Reactome R-SCE-5083620 1 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-SCE-5083620.1 CSNK2A1:CSNK2A2 Reactome DB_ID: 10917035 1 1 Reactome Database ID Release 83 10917035 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=10917035 Reactome R-SCE-5083623 1 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-SCE-5083623.1 Reactome Database ID Release 83 10917037 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=10917037 Reactome R-SCE-5083624 1 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-SCE-5083624.1 2 Reactome Database ID Release 83 10917039 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=10917039 Reactome R-SCE-201711 1 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-SCE-201711.1 Reactome Database ID Release 83 10917040 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=10917040 Reactome Database ID Release 83 10925489 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=10925489 Reactome R-SCE-8850945 1 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-SCE-8850945.1 Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. S370 and S385 are the main CK2 phosphorylation sites in PTEN (Torres and Pulido 2001, Miller et al. 2002). CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002). 11035045 Pubmed 2001 The tumor suppressor PTEN is phosphorylated by the protein kinase CK2 at its C terminus. Implications for PTEN stability to proteasome-mediated degradation Torres, J Pulido, R J. Biol. Chem. 276:993-8 12297295 Pubmed 2002 Direct identification of PTEN phosphorylation sites Miller, Susan J Lou, David Y Seldin, David C Lane, William S Neel, Benjamin G FEBS Lett. 528:145-53 Reactome Database ID Release 83 10930617 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=10930617 Reactome R-SCE-8948751 1 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-SCE-8948751.1 PTEN protein stability is regulated by ubiquitin ligases, such as NEDD4, WWP2, STUB1 (CHIP), XIAP, MKRN1 and RNF146, which polyubiquitinate PTEN in response to different stimuli and thus target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Maddika et al. 2011, Ahmed et al. 2012, Lee et al. 2015, Li et al. 2015). Several ubiquitin proteases, such as USP13 and OTUD3, can remove polyubiquitin chains from PTEN and rescue it from degradation (Zhang et al. 2013, Yuan et al. 2015). TRIM27 (RFP) is an E3 ubiquitin ligase that polyubiquitinates PTEN on multiple lysines in the C2 domain of PTEN using K27 linkage between ubiquitin molecules. TRIM27 mediated ubiquitination inhibits PTEN lipid phosphatase activity, but does not affect PTEN protein localization or stability (Lee et al. 2013).<br>PTEN phosphorylation by the tyrosine kinase FRK (RAK) inhibits NEDD4 mediated polyubiquitination and subsequent degradation of PTEN, thus increasing PTEN half life. FRK mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase 2 (CK2) mediated phosphorylation of the C-terminus of PTEN on multiple serine and threonine residues increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).<br>PREX2, a RAC1 guanine nucleotide exchange factor (GEF) can binds to PTEN and inhibit its catalytic activity (Fine et al. 2009). 25547115 Pubmed 2015 Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth Li, N Zhang, Yajie Han, Xin Liang, Ke Wang, Jiadong Feng, Lin Wang, W Songyang, Z Lin, Chunru Yang, Liuqing Yu, Yonghao Chen, J Genes Dev. 29:157-70 17218260 Pubmed 2007 NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN Wang, Xinjiang Trotman, Lloyd C Koppie, Theresa Alimonti, Andrea Chen, Zhenbang Gao, Zhonghua Wang, Junru Erdjument-Bromage, H Tempst, P Cordon-Cardo, Carlos Pandolfi, Pier Paolo Jiang, Xuejun Cell 128:129-39 19729658 Pubmed 2009 Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a Fine, Barry Hodakoski, Cindy Koujak, Susan Su, Tao Saal, Lao H Maurer, Matthew Hopkins, Benjamin Keniry, Megan Sulis, ML Mense, Sarah Hibshoosh, Hanina Parsons, R Science 325:1261-5 21532586 Pubmed 2011 WWP2 is an E3 ubiquitin ligase for PTEN Maddika, Subbareddy Kavela, Sridhar Rani, Neelam Palicharla, Vivek Reddy Pokorny, Jenny L Sarkaria, Jann N Chen, J Nat. Cell Biol. 13:728-33 22427670 Pubmed 2012 The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation Ahmed, Syed Feroj Deb, Satamita Paul, Indranil Chatterjee, Anirban Mandal, Tapashi Chatterjee, Uttara Ghosh, Mrinal K J. Biol. Chem. 287:15996-6006 24367090 Pubmed 2014 Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis Hodakoski, Cindy Hopkins, Benjamin D Barrows, Douglas Mense, Sarah M Keniry, Megan Anderson, Karen E Kern, Philip A Hawkins, Phillip T Stephens, Len R Parsons, R Proc. Natl. Acad. Sci. U.S.A. 111:155-60 19345329 Pubmed 2009 Rak functions as a tumor suppressor by regulating PTEN protein stability and function Yim, Eun-Kyoung Peng, Guang Dai, Hui Hu, Ruozhen Li, Kaiyi Lu, Yiling Mills, Gordon B Meric-Bernstam, Funda Hennessy, Bryan T Craven, Rolf J Lin, Shiaw-Yih Cancer Cell 15:304-14 Reactome Database ID Release 83 10930587 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=10930587 Reactome R-SCE-6807070 1 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-SCE-6807070.1 PTEN is regulated at the level of gene transcription, mRNA translation, localization and protein stability.<p>Transcription of the PTEN gene is regulated at multiple levels. Epigenetic repression involves the recruitment of Mi-2/NuRD upon SALL4 binding to the PTEN promoter (Yang et al. 2008, Lu et al. 2009) or EVI1-mediated recruitment of the polycomb repressor complex (PRC) to the PTEN promoter (Song et al. 2009, Yoshimi et al. 2011). Transcriptional regulation is also elicited by negative regulators, including NR2E1:ATN1 (atrophin-1) complex, JUN (c-Jun), SNAIL and SLUG (Zhang et al. 2006, Vasudevan et al. 2007, Escriva et al. 2008, Uygur et al. 2015) and positive regulators such as TP53 (p53), MAF1, ATF2, EGR1 or PPARG (Stambolic et al. 2001, Virolle et al. 2001, Patel et al. 2001, Shen et al. 2006, Li et al. 2016).<p>MicroRNAs miR-26A1, miR-26A2, miR-22, miR-25, miR-302, miR-214, miR-17-5p, miR-19 and miR-205 bind PTEN mRNA and inhibit its translation into protein. These microRNAs are altered in cancer and can account for changes in PTEN levels (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Huse et al. 2009, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Cai et al. 2013). In addition, coding and non-coding RNAs can prevent microRNAs from binding to PTEN mRNA. These RNAs are termed competing endogenous RNAs or ceRNAs. Transcripts of the pseudogene PTENP1 and mRNAs transcribed from SERINC1, VAPA and CNOT6L genes exhibit this activity (Poliseno, Salmena, Zhang et al. 2010, Tay et al. 2011, Tay et al. 2014).<p>PTEN can translocate from the cytosol to the nucleus after undergoing monoubiquitination. PTEN's ability to localize to the nucleus contributes to its tumor suppressive role (Trotman et al. 2007). The ubiquitin protease USP7 (HAUSP) targets monoubiquitinated PTEN in the nucleus, resulting in PTEN deubiquitination and nuclear exclusion. PML, via an unknown mechanism that involves USP7- and PML-interacting protein DAXX, inhibits USP7-mediated deubiquitination of PTEN, thus promoting PTEN nuclear localization. Disruption of PML function in acute promyelocytic leukemia, through a chromosomal translocation that results in expression of a fusion protein PML-RARA, leads to aberrant PTEN localization (Song et al. 2008).<p>Several ubiquitin ligases, including NEDD4, WWP2, STUB1 (CHIP), RNF146, XIAP and MKRN1, polyubiquitinate PTEN and target it for proteasome-mediated degradation (Wang et al. 2007, Van Themsche et al. 2009, Ahmed et al. 2011, Maddika et al. 2011, Lee et al. 2015, Li et al. 2015). The ubiquitin proteases USP13 and OTUD3, frequently down-regulated in breast cancer, remove polyubiquitin chains from PTEN, thus preventing its degradation and increasing its half-life (Zhang et al. 2013, Yuan et al. 2015). The catalytic activity of PTEN is negatively regulated by PREX2 binding (Fine et al. 2009, Hodakoski et al. 2014) and TRIM27-mediated ubiquitination (Lee et al. 2013), most likely through altered PTEN conformation.<p>In addition to ubiquitination, PTEN also undergoes SUMOylation (Gonzalez-Santamaria et al. 2012, Da Silva Ferrada et al. 2013, Lang et al. 2015, Leslie et al. 2016). SUMOylation of the C2 domain of PTEN may regulate PTEN association with the plasma membrane (Shenoy et al. 2012) as well as nuclear localization of PTEN (Bassi et al. 2013, Collaud et al. 2016). PIASx-alpha, a splicing isorom of E3 SUMO-protein ligase PIAS2 has been implicated in PTEN SUMOylation (Wang et al. 2014). SUMOylation of PTEN may be regulated by activated AKT (Lin et al. 2016). Reactions describing PTEN SUMOylation will be annotated when mechanistic details become available.<p>Phosphorylation affects the stability and activity of PTEN. FRK tyrosine kinase (RAK) phosphorylates PTEN on tyrosine residue Y336, which increases PTEN half-life by inhibiting NEDD4-mediated polyubiquitination and subsequent degradation of PTEN. FRK-mediated phosphorylation also increases PTEN enzymatic activity (Yim et al. 2009). Casein kinase II (CK2) constitutively phosphorylates the C-terminal tail of PTEN on serine and threonine residues S370, S380, T382, T383 and S385. CK2-mediated phosphorylation increases PTEN protein stability (Torres and Pulido 2001) but results in ~30% reduction in PTEN lipid phosphatase activity (Miller et al. 2002).<p>PTEN localization and activity are affected by acetylation of its lysine residues (Okumura et al. 2006, Ikenoue et al. 2008, Meng et al. 2016). PTEN can undergo oxidation, which affects its function, but the mechanism is poorly understood (Tan et al. 2015, Shen et al. 2015, Verrastro et al. 2016). 22000013 Pubmed 2011 Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs Tay, Yvonne Kats, Lev Salmena, Leonardo Weiss, Dror Tan, Shen Mynn Ala, Ugo Karreth, Florian Poliseno, Laura Provero, Paolo Di Cunto, Ferdinando Lieberman, Judy Rigoutsos, Isidore Pandolfi, Pier Paolo Cell 147:344-57 23888040 Pubmed 2013 Nuclear PTEN controls DNA repair and sensitivity to genotoxic stress Bassi, C Ho, J Srikumar, T Dowling, R J O Gorrini, C Miller, S J Mak, T W Neel, B G Raught, B Stambolic, V Science 341:395-9 24344134 Pubmed 2014 PIASxα ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase Wang, Weibin Chen, Yifan Wang, Shuya Hu, Ningguang Cao, Zhengyi Wang, Wengong Tong, Tanjun Zhang, Xiaowei J. Biol. Chem. 289:3217-30 25867063 Pubmed 2016 SUMO modification of Akt regulates global SUMOylation and substrate SUMOylation specificity through Akt phosphorylation of Ubc9 and SUMO1 Lin, C H Liu, S Y Lee, E H Y Oncogene 35:595-607 19487573 Pubmed 2009 The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivo Huse, Jason T Brennan, Cameron Hambardzumyan, Dolores Wee, Boyoung Pena, John Rouhanifard, Sara H Sohn-Lee, Cherin le Sage, Carlos Agami, Reuven Tuschl, Thomas Holland, Eric C Genes Dev. 23:1327-37 20388916 Pubmed 2010 Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation Poliseno, Laura Salmena, Leonardo Riccardi, Luisa Fornari, Alessandro Song, MS Hobbs, Robin M Sportoletti, Paolo Varmeh, Shorheh Egia, Ainara Fedele, Giuseppe Rameh, Lucia Loda, Massimo Pandolfi, Pier Paolo Sci Signal 3:ra29 23073177 Pubmed 2012 Membrane association of the PTEN tumor suppressor: electrostatic interaction with phosphatidylserine-containing bilayers and regulatory role of the C-terminal tail Shenoy, Siddharth S Nanda, Hirsh Lösche, Mathias J. Struct. Biol. 180:394-408 25224693 Pubmed 2015 Analysis of PTEN ubiquitylation and SUMOylation using molecular traps Lang, Valérie Aillet, Fabienne Da Silva-Ferrada, Elisa Xolalpa, Wendy Zabaleta, Lorea Rivas, Carmen Rodriguez, Manuel S Methods 77:112-8 26561776 Pubmed 2016 Reversible oxidation of phosphatase and tensin homolog (PTEN) alters its interactions with signaling and regulatory proteins Verrastro, Ivan Tveen-Jensen, Karina Woscholski, Rudiger Spickett, Corinne M Pitt, Andrew R Free Radic. Biol. Med. 90:24-34 26862215 Pubmed 2016 The PTEN protein: cellular localization and post-translational regulation Leslie, Nick R Kriplani, Nisha Hermida, Miguel A Alvarez-Garcia, Virginia Wise, Helen M Biochem. Soc. Trans. 44:273-8 18199536 Pubmed 2008 MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN Yang, Hua Kong, William He, Lili Zhao, Jian-Jun O'Donnell, Joshua D Wang, Jiawang Wenham, Robert M Coppola, Domenico Kruk, Patricia A Nicosia, Santo V Cheng, Jin Q Cancer Res. 68:425-33 17681183 Pubmed 2007 MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer Meng, Fanyin Henson, Roger Wehbe-Janek, Hania Ghoshal, Kalpana Jacob, Samson T Patel, Tushar Gastroenterology 133:647-58 23856247 Pubmed 2013 miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer Cai, Junchao Fang, Lishan Huang, Yongbo Li, Rong Yuan, Jie Yang, Y Zhu, Xun Chen, Baixue Wu, Jueheng Li, Mengfeng Cancer Res. 73:5402-15 20577206 Pubmed 2010 A coding-independent function of gene and pseudogene mRNAs regulates tumour biology Poliseno, Laura Salmena, Leonardo Zhang, Jiangwen Carver, Brett Haveman, William J Pandolfi, Pier Paolo Nature 465:1033-8 26279303 Pubmed 2016 PTEN activation through K163 acetylation by inhibiting HDAC6 contributes to tumour inhibition Meng, Z Jia, L-F Gan, Y-H Oncogene 35:2333-44 16829519 Pubmed 2006 PCAF modulates PTEN activity Okumura, Koichi Mendoza, Michelle Bachoo, Robert M DePinho, Ronald A Cavenee, Webster K Furnari, Frank B J. Biol. Chem. 281:26562-8 23604351 Pubmed 2013 Analysis of SUMOylated proteins using SUMO-traps Da Silva-Ferrada, Elisa Xolalpa, Wendy Lang, Valérie Aillet, Fabienne Martin-Ruiz, Itziar de la Cruz-Herrera, Carlos F Lopitz-Otsoa, Fernando Carracedo, Arkaitz Goldenberg, SJ Rivas, Carmen England, Patrick Rodriguez, Manuel S Sci Rep 3:1690 18757404 Pubmed 2008 PTEN acetylation modulates its interaction with PDZ domain Ikenoue, T Inoki, Ken Zhao, B Guan, KL Cancer Res. 68:6908-12 23419514 Pubmed 2013 RFP-mediated ubiquitination of PTEN modulates its effect on AKT activation Lee, James T Shan, Jing Zhong, Jiayun Li, Muyang Zhou, Brenda Zhou, Amanda Parsons, R Gu, Wei Cell Res. 23:552-64 20080666 Pubmed 2010 Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship Kim, Hyunsoo Huang, Wei Jiang, Xiuli Pennicooke, Brenton Park, Peter J Johnson, Mark D Proc. Natl. Acad. Sci. U.S.A. 107:2183-8 24270891 Pubmed 2013 Deubiquitylation and stabilization of PTEN by USP13 Zhang, Jinsong Zhang, Peijing Wei, Yongkun Piao, Hai-Long Wang, W Maddika, Subbareddy Wang, Min Chen, Dahu Sun, Yutong Hung, Mien-Chie Chen, J Ma, Li Nat. Cell Biol. 15:1486-94 25737250 Pubmed 2015 Differential thiol oxidation of the signaling proteins Akt, PTEN or PP2A determines whether Akt phosphorylation is enhanced or inhibited by oxidative stress in C2C12 myotubes derived from skeletal muscle Tan, Pearl Lin Shavlakadze, Tea Grounds, Miranda D Arthur, Peter G Int. J. Biochem. Cell Biol. 62:72-9 26415504 Pubmed 2015 AIF inhibits tumor metastasis by protecting PTEN from oxidation Shen, Shao-Ming Guo, Meng Xiong, Zhong Yu, Yun Zhao, Xu-Yun Zhang, Fei-Fei Chen, Guo-Qiang EMBO Rep. 16:1563-80 18327259 Pubmed 2008 Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes Xiao, Changchun Srinivasan, Lakshmi Calado, Dinis Pedro Patterson, Heide Christine Zhang, Baochun Wang, Jing Henderson, Joel M Kutok, Jeffrey L Rajewsky, Klaus Nat. Immunol. 9:405-14 23013792 Pubmed 2012 Regulation of the tumor suppressor PTEN by SUMO González-Santamaría, J Campagna, M Ortega-Molina, A Marcos-Villar, L de la Cruz-Herrera, C F González, D Gallego, P Lopitz-Otsoa, F Esteban, M Rodriguez, M S Serrano, M Rivas, C Cell Death Dis 3:e393 26280536 Pubmed 2015 Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis Yuan, Lin Lv, Yanrong Li, Hongchang Gao, Haidong Song, Shanshan Zhang, Yuan Xing, Guichun Kong, Xiangzhen Wang, Lijing Li, Yang Zhou, Tao Gao, Daming Xiao, Zhi-Xiong Yin, Yuxin Wei, Wenyi He, Fuchu Zhang, Lingqiang Nat. Cell Biol. 17:1169-81 25884169 Pubmed 2015 Lung neuroendocrine tumors: correlation of ubiquitinylation and sumoylation with nucleo-cytosolic partitioning of PTEN Collaud, Stéphane Tischler, Verena Atanassoff, Andrej Wiedl, Thomas Komminoth, Paul Oehlschlegel, Christian Weder, Walter Soltermann, A BMC Cancer 15:74 24429633 Pubmed 2014 The multilayered complexity of ceRNA crosstalk and competition Tay, Yvonne Rinn, John Pandolfi, Pier Paolo Nature 505:344-52 Reactome Database ID Release 83 10929813 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=10929813 Reactome R-SCE-1257604 1 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-SCE-1257604.1 GENE ONTOLOGY GO:0051897 Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007. 17604717 Pubmed 2007 AKT/PKB signaling: navigating downstream Manning, BD Cantley, Lewis C Cell 129:1261-74 DAG and IP3 signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.11.13 DAG stimulates protein kinase C-delta This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome PKC-delta/epsilon Reactome DB_ID: 10910022 PRKCD P24583 Reactome DB_ID: 10910018 UniProt:P24583 UniProt P24583 1 EQUAL 676 EQUAL Reactome Database ID Release 83 10910018 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=10910018 Reactome R-SCE-58200 1 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-SCE-58200.1 PRKCE P24583 Reactome DB_ID: 10910020 1 EQUAL 737 EQUAL Reactome Database ID Release 83 10910020 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=10910020 Reactome R-SCE-58202 1 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-SCE-58202.1 Reactome Database ID Release 83 10910022 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=10910022 Reactome R-SCE-198276 1 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-SCE-198276.1 3 3 Converted from EntitySet in Reactome Phospho-PKC-delta/epsilon Reactome DB_ID: 10910034 P24583 phospho-p-T507,S645,S664-PRKCD(1-676) Reactome DB_ID: 10910027 507 EQUAL 645 EQUAL 664 EQUAL 1 EQUAL 676 EQUAL Reactome Database ID Release 83 10910027 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=10910027 Reactome R-SCE-198294 1 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-SCE-198294.1 P24583 phospho-p-T566,T710,S729-PRKCE Reactome DB_ID: 10910032 566 EQUAL 710 EQUAL 729 EQUAL 1 EQUAL 737 EQUAL Reactome Database ID Release 83 10910032 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=10910032 Reactome R-SCE-198260 1 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-SCE-198260.1 Reactome Database ID Release 83 10910034 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=10910034 Reactome R-SCE-198265 1 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-SCE-198265.1 ACTIVATION GENE ONTOLOGY GO:0004697 Reactome Database ID Release 83 10910035 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=10910035 Reactome Database ID Release 83 10910037 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=10910037 Reactome R-SCE-198314 1 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-SCE-198314.1 Diacylglycerol (DAG) positively regulates the autophosphorylation of protein kinase C-delta (PKC-delta), which stimulates ERK1/2 and triggers neurite outgrowth. DAG also stimulates the translocation of PKC from the cytosol to the plasma membrane. PKC-delta contributes to growth factor specificity and response to neuronal cells by promoting cell-type-specific differences in growth factor signalling. DAG can also activate PKC-epsilon in the same manner (Newton 2001). 16678913 Pubmed 2006 PKD at the crossroads of DAG and PKC signaling Wang, Qiming J Trends Pharmacol. Sci. 27:317-23 11749377 Pubmed 2001 Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions Newton, A C Chem. Rev. 101:2353-64 ACTIVATION Reactome Database ID Release 83 1489502 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=1489502 Reactome R-HSA-1489502 1 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-1489502.1 DAG DAGs diacylglycerols diglyceride Reactome DB_ID: 112275 diglyceride [ChEBI:18035] diglyceride ChEBI CHEBI:18035 Reactome Database ID Release 83 112275 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=112275 Reactome R-ALL-112275 3 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-ALL-112275.3 COMPOUND C00165 CaM pathway This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Calmodulin induced events This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PKA-mediated phosphorylation of CREB This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PKA activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT cAMP binds PKA tetramer This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PKA tetramer Reactome DB_ID: 10908231 Converted from EntitySet in Reactome PRKACA,PRKACB,PRKACG PKA catalytic subunit Reactome DB_ID: 10908229 PRKACA P06245 Reactome DB_ID: 10908215 UniProt:P06245 UniProt P06245 2 EQUAL 351 EQUAL Reactome Database ID Release 83 10908215 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=10908215 Reactome R-SCE-57844 1 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-SCE-57844.1 Converted from EntitySet in Reactome Homologues of PRKACB Reactome DB_ID: 10908227 PRKACB P05986 Reactome DB_ID: 10908220 UniProt:P05986 UniProt P05986 2 EQUAL 351 EQUAL Reactome Database ID Release 83 10908220 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=10908220 Reactome R-SCE-57846 1 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-SCE-57846.1 PRKACB P06244 Reactome DB_ID: 10908225 UniProt:P06244 UniProt P06244 2 EQUAL 351 EQUAL Reactome Database ID Release 83 10908225 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=10908225 Reactome R-SCE-57846-2 1 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-SCE-57846-2.1 Reactome Database ID Release 83 10908227 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=10908227 Reactome R-SCE-57846-3 1 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-SCE-57846-3.1 Reactome Database ID Release 83 10908229 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=10908229 Reactome R-SCE-111920 1 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-SCE-111920.1 2 Converted from EntitySet in Reactome PKA regulatory subunit Reactome DB_ID: 10908210 P07278 PRKAR2A Reactome DB_ID: 10908206 UniProt:P07278 UniProt P07278 2 EQUAL 404 EQUAL Reactome Database ID Release 83 10908206 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=10908206 Reactome R-SCE-57840 1 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-SCE-57840.1 P07278 PRKAR2B Reactome DB_ID: 10908208 2 EQUAL 418 EQUAL Reactome Database ID Release 83 10908208 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=10908208 Reactome R-SCE-57842 1 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-SCE-57842.1 Reactome Database ID Release 83 10908210 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=10908210 Reactome R-SCE-111921 1 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-SCE-111921.1 2 Reactome Database ID Release 83 10908231 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=10908231 Reactome R-SCE-111922 1 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-SCE-111922.1 cAMP Cyclic adenylic acid 3',5'-cyclic AMP Cyclic AMP Adenosine 3',5'-phosphate Reactome DB_ID: 30389 3',5'-cyclic AMP(1-) [ChEBI:58165] 3',5'-cyclic AMP(1-) adenosine 3',5'-cyclic monophosphate anion adenosine 3',5'-phosphate 3',5'-cyclic AMP anion 3',5'-cyclic AMP adenosine 3',5'-cyclic monophosphate(1-) adenosine 3',5'-cyclic monophosphate ChEBI CHEBI:58165 Reactome Database ID Release 83 30389 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=30389 Reactome R-ALL-30389 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-ALL-30389.4 COMPOUND C00575 4 PKA tetramer:4xcAMP Reactome DB_ID: 10908233 1 4 Reactome Database ID Release 83 10908233 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=10908233 Reactome R-SCE-8951729 1 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-SCE-8951729.1 Reactome Database ID Release 83 10927116 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=10927116 Reactome R-SCE-8951727 1 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-SCE-8951727.1 Protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The isoform activated in response to glucagon signaling is not known. <br><br>PKA kinase is a tetramer of two regulatory and two catalytic subunits. The regulatory subunits block the activity of the catalytic subunits. <br><br>cAMP binds the regulatory subunits, which leads to dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit. 16407073 Pubmed 2006 Dynamic binding of PKA regulatory subunit RI alpha Gullingsrud, J Kim, C Taylor, SS McCammon, JA Structure 14:141-9 LEFT-TO-RIGHT cAMP induces dissociation of inactive PKA tetramers This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> cAMP:PKA regulatory subunit Reactome DB_ID: 10908235 2 4 Reactome Database ID Release 83 10908235 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=10908235 Reactome R-SCE-111923 1 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-SCE-111923.1 2 Reactome Database ID Release 83 10908237 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=10908237 Reactome R-SCE-111925 1 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-SCE-111925.1 The protein kinase A (PKA) regulatory subunit isoforms differ in their tissue specificity and functional characteristics. The specific isoform activated in response to glucagon signaling is not known. The PKA kinase is a tetramer of two regulatory and two catalytic subunits. The regulatory subunits block the catalytic subunits. Binding of cAMP to the regulatory subunit triggers dissociation of the tetramer into two active dimers made up of a regulatory and a catalytic subunit. Reactome Database ID Release 83 10929541 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=10929541 Reactome R-SCE-163615 1 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-SCE-163615.1 GENE ONTOLOGY GO:0034199 A number of inactive tetrameric PKA holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. When cAMP binds to two specific binding sites on the regulatory subunits, these undergo a conformational change that causes the dissociation of a dimer of regulatory subunits bound to four cAMP from two monomeric, catalytically active PKA subunits. 2165385 Pubmed 1990 cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes Taylor, SS Buechler, JA Yonemoto, W Annu Rev Biochem 59:971-1005 Reactome Database ID Release 83 10929543 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=10929543 Reactome R-SCE-111931 1 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-SCE-111931.1 Cyclic adenosine 3',5'-monophosphate (cAMP) induces gene transcription through activation of cAMP-dependent protein kinase (PKA), and subsequent phosphorylation of the transcription factor cAMP response element-binding protein, CREB, at serine-133. 15337521 Pubmed 2004 What turns CREB on? Johannessen, M Delghandi, MP Moens, U Cell Signal 16:1211-27 16125054 Pubmed 2005 The cAMP signalling pathway activates CREB through PKA, p38 and MSK1 in NIH 3T3 cells Delghandi, MP Johannessen, M Moens, U Cell Signal 17:1343-51 Reactome Database ID Release 83 10929545 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=10929545 Reactome R-SCE-111933 1 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-SCE-111933.1 One important physiological role for Calmodulin is the regulation of adenylylcyclases. Four of the nine known adenylylcyclases are calcium sensitive, in particular type 8 (AC8). 15381755 Pubmed 2004 Why calcium-stimulated adenylyl cyclases? Ferguson, GD Storm, DR Physiology (Bethesda) 19:271-6 Reactome Database ID Release 83 10929547 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=10929547 Reactome R-SCE-111997 1 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-SCE-111997.1 Calmodulin (CaM) is a small acidic protein that contains four EF-hand motifs, each of which can bind a calcium ion, therefore it can bind up to four calcium ions. The protein has two approximately symmetrical domains, separated by a flexible hinge region. Calmodulin is the prototypical example of the EF-hand family of Ca2+-sensing proteins. Changes in intracellular Ca2+ concentration regulate calmodulin in three distinct ways. First, by directing its subcellular distribution. Second, by promoting association with different target proteins. Third, by directing a variety of conformational states in calmodulin that result in target-specific activation. Calmodulin binds and activates several effector protein (e.g. the CaM-dependent adenylyl cyclases, phosphodiesterases, protein kinases and the protein phosphatase calcineurin). 10884684 Pubmed 2000 Calmodulin: a prototypical calcium sensor Chin, D Means, AR Trends Cell Biol 10:322-8 Reactome Database ID Release 83 10929549 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=10929549 Reactome R-SCE-1489509 1 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-SCE-1489509.1 This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events. 16260143 Pubmed 2005 Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling Patterson, RL van Rossum, DB Nikolaidis, N Gill, DL Snyder, SH Trends Biochem Sci 30:688-97 Reactome Database ID Release 83 10929551 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=10929551 Reactome R-SCE-9006925 1 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-SCE-9006925.1 Second messengers are generated within the cell as a downstream step in signal transduction cascades initiated by the interaction of an external stimulus with a cell surface receptor. Common second messengers include DAG, cAMP, cGMP, IP3, Ca2+ and phosphatidylinositols (reviewed in Kang et al, 2015; Raker et al, 2016; Li and Marshall, 2015; Pinto et al, 2015; Ahmad et al, 2015). 25056711 Pubmed 2015 Cyclic nucleotide phosphodiesterases: important signaling modulators and therapeutic targets Ahmad, F Murata, T Shimizu, K Degerman, E Maurice, D Manganiello, V Oral Dis 21:e25-50 27065076 Pubmed 2016 The cAMP Pathway as Therapeutic Target in Autoimmune and Inflammatory Diseases Raker, Verena Katharina Becker, Christian Steinbrink, Kerstin Front Immunol 7:123 26588873 Pubmed 2016 Roles of phosphoinositide-specific phospholipase Cγ1 in brain development Kang, Du-Seock Yang, Yong Ryoul Lee, Cheol Kim, SaetByeol Ryu, Sung Ho Suh, PG Adv Biol Regul 60:167-73 26275497 Pubmed 2015 Calcium signaling and cell proliferation Pinto, Mauro Cunha Xavier Kihara, Alexandre Hiroaki Goulart, Vânia A M Tonelli, Fernanda M P Gomes, Katia N Ulrich, Henning Resende, Rodrigo R Cell. Signal. 27:2139-49 26922871 Pubmed 2016 Signalling at membrane contact sites: two membranes come together to handle second messengers Levine, Tim P Patel, Sandip Curr. Opin. Cell Biol. 39:77-83