BioPAX pathway converted from "CD28 dependent PI3K/Akt signaling" in the Reactome database.

CD28 dependent PI3K/Akt signaling

PI3Ks can be activated by a number of different receptors, including the TcR (T cell receptor), co-stimulatory receptors (CD28), cytokine receptors and chemokine receptors. However, the specific roles of PI3Ks downstream of these receptors vary. CD28 contains the YMNM consensus PI3K-binding motif, and PI3K recruitment by CD28 contributes to or complements TCR-dependent PI3K signaling. Activation of PI3K promotes PIP3 production at the plasma membrane and several potential target molecules for this phospholipid have been implicated in PI3K pathways downstream of the TcR and CD28. Of these targets, at least Vav and Akt have been implicated in CD28 costimulation of T cell activation. AKT/PKB connects PI3K to signaling pathways that promote cytokine transcription, survival, cell-cycle entry and growth.

Authored: Garapati, P V, 2008-12-16 11:12:19Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33Edited: Garapati, P V, 2008-12-16 11:12:19

PI3K binds CD28

PI3K inducibly associates with CD28: the SH2 domains of the PI3K p85 adaptor subunit interact with a cytoplasmic YMNM consensus motif at residues 173-176 of CD28.

Authored: Garapati, P V, 2008-12-16 11:12:19Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33Edited: Garapati, P V, 2008-12-16 11:12:19

Reactome DB_ID: 388777

plasma membraneGO0005886phospho CD28:B7-1/B7-2 [plasma membrane]

phospho CD28:B7-1/B7-2

Converted from EntitySet in Reactome

Reactome DB_ID: 389329

cytosolGO0005829

LCK, FYN [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityLCK [cytosol]FYN [cytosol]

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtP06239UniProtP06241

Reactome DB_ID: 388778

Phospho CD28 homodimer [plasma membrane]

Phospho CD28 homodimer

Reactome DB_ID: 388756

UniProt:P10747 CD28

CD28

CD28FUNCTION Involved in T-cell activation, the induction of cell proliferation and cytokine production and promotion of T-cell survival. Enhances the production of IL4 and IL10 in T-cells in conjunction with TCR/CD3 ligation and CD40L costimulation (PubMed:8617933). Isoform 3 enhances CD40L-mediated activation of NF-kappa-B and kinases MAPK8 and PAK2 in T-cells (PubMed:15067037).SUBUNIT Homodimer; disulfide-linked. Interacts with DUSP14. Binds to CD80/B7-1 and CD86/B7-2/B70. Interacts with GRB2. Isoform 3 interacts with CD40LG (PubMed:15067037).TISSUE SPECIFICITY Expressed in T-cells and plasma cells, but not in less mature B-cells.PTM CD40LG induces tyrosine phosphorylation of isoform 3.

UniProtP10747

O4'-phospho-L-tyrosine at 191

191

EQUAL

O4'-phospho-L-tyrosine [MOD:00048]

Chain Coordinates

EQUAL

220

EQUAL

Reactome Database ID Release 70388778Database 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=388778ReactomeR-HSA-388778

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-388778.1Converted from EntitySet in Reactome

Reactome DB_ID: 388762

B7-1 homodimer/ B7-2 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCD86 [plasma membrane]

UniProtP42081Reactome Database ID Release 70388777Database 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=388777ReactomeR-HSA-388777

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-388777.1

Reactome DB_ID: 198379

PI3K alpha [cytosol]

PI3K alpha

Converted from EntitySet in Reactome

Reactome DB_ID: 391342

PI3K-regulatory subunits [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPIK3R1 [cytosol]

UniProtP27986

Reactome DB_ID: 74787

UniProt:P42336 PIK3CA

PIK3CA

PIK3CAFUNCTION Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Also has serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS. Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity).SUBUNIT Heterodimer of a catalytic subunit PIK3CA and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3) (PubMed:26593112). Interacts with IRS1 in nuclear extracts (By similarity). Interacts with RUFY3 (By similarity). Interacts with RASD2 (By similarity). Interacts with APPL1. Interacts with HRAS and KRAS (By similarity). Interaction with HRAS/KRAS is required for PI3K pathway signaling and cell proliferation stimulated by EGF and FGF2 (By similarity). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467).DOMAIN The PI3K-ABD domain and the PI3K-RBD domain interact with the PI3K/PI4K kinase domain. The C2 PI3K-type domain may facilitate the recruitment to the plasma membrane. The inhibitory interactions with PIK3R1 are mediated by the PI3K-ABD domain and the C2 PI3K-type domain with the iSH2 (inter-SH2) region of PIK3R1, and the C2 PI3K-type domain, the PI3K helical domain, and the PI3K/PI4K kinase domain with the nSH2 (N-terminal SH2) region of PIK3R1.DISEASE PIK3CA mutations are involved in various type of cancer. Most of the cancer-associated mutations are missense mutations and map to one of the three hotspots: Glu-542; Glu-545 and His-1047. Mutated isoforms participate in cellular transformation and tumorigenesis induced by oncogenic receptor tyrosine kinases (RTKs) and HRAS/KRAS. Interaction with HRAS/KRAS is required for Ras-driven tumor formation. Mutations increasing the lipid kinase activity are required for oncogenic signaling. The protein kinase activity may not be required for tumorigenesis.MISCELLANEOUS The avian sarcoma virus 16 genome encodes an oncogene derived from PIK3CA.SIMILARITY Belongs to the PI3/PI4-kinase family.

UniProtP42336

EQUAL

1068

EQUAL

Reactome Database ID Release 70198379Database 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=198379ReactomeR-HSA-198379

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-198379.1

Reactome DB_ID: 388783

CD28:PI3K [plasma membrane]

CD28:PI3K

Reactome DB_ID: 388777

Reactome DB_ID: 198379

Reactome Database ID Release 70388783Database 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=388783ReactomeR-HSA-388783

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-388783.1Reactome Database ID Release 70388832Database 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=388832ReactomeR-HSA-388832

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-388832.18621607Pubmed1996Two distinct intracytoplasmic regions of the T-cell adhesion molecule CD28 participate in phosphatidylinositol 3-kinase associationPagès, FRagueneau, MKlasen, SBattifora, MCouez, DSweet, RTruneh, AWard, SGOlive, DJ Biol Chem 271:9403-912670391Pubmed2003The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3Kane, LPWeiss, AImmunol Rev 192:7-20

2.7.1.153

CD28 bound PI3K phosphorylates PIP2 to PIP3

PI3K enzyme bound to co-stimulatory protein CD28 catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). This PIP3 acts as a membrane anchor for the downstream proteins like PDK1 and PKB.

Authored: Garapati, P V, 2008-12-16 11:12:19Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33Edited: Garapati, P V, 2008-12-16 11:12:19

Reactome DB_ID: 179856

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348]

1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate

PIP2

ChEBI18348

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 179838

1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618]

1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate

PIP3

ChEBI16618

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

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

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 388783

GO0046934

GO molecular function

Reactome Database ID Release 70389160Database 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=389160Reactome Database ID Release 70389158Database 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=389158ReactomeR-HSA-389158

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-389158.112660731Pubmed2003The role of PI3K in immune cellsKoyasu, SNat Immunol 4:313-9

PIP3 recruits PDPK1 to the membrane

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).

Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37Reviewed: Thorpe, Lauren, 2012-08-13Reviewed: Yuzugullu, Haluk, 2012-08-13Reviewed: Zhao, Jean J, 2012-08-13Edited: Matthews, L, 2012-08-03

Reactome DB_ID: 179838

Reactome DB_ID: 202210

UniProt:O15530 PDPK1

PDPK1

PDPK1PDK1FUNCTION Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.ACTIVITY REGULATION Homodimerization regulates its activity by maintaining the kinase in an autoinhibitory conformation. NPRL2 down-regulates its activity by interfering with tyrosine phosphorylation at the Tyr-9, Tyr-373 and Tyr-376 residues. The 14-3-3 protein YWHAQ acts as a negative regulator by association with the residues surrounding the Ser-241 residue. STRAP positively regulates its activity by enhancing its autophosphorylation and by stimulating its dissociation from YWHAQ. SMAD2, SMAD3, SMAD4 and SMAD7 also positively regulate its activity by stimulating its dissociation from YWHAQ. Activated by phosphorylation on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin.SUBUNIT Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-241 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.TISSUE SPECIFICITY Appears to be expressed ubiquitously. The Tyr-9 phosphorylated form is markedly increased in diseased tissue compared with normal tissue from lung, liver, colon and breast.INDUCTION Stimulated by insulin, and the oxidants hydrogen peroxide and peroxovanadate.DOMAIN The PH domain plays a pivotal role in the localization and nuclear import of PDPK1 and is also essential for its homodimerization.DOMAIN The PIF-pocket is a small lobe in the catalytic domain required by the enzyme for the binding to the hydrophobic motif of its substrates. It is an allosteric regulatory site that can accommodate small compounds acting as allosteric inhibitors.PTM Phosphorylation on Ser-241 in the activation loop is required for full activity. PDPK1 itself can autophosphorylate Ser-241, leading to its own activation. Autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2 (By similarity). Tyr-9 phosphorylation is critical for stabilization of both PDPK1 and the PDPK1/SRC complex via HSP90-mediated protection of PDPK1 degradation. Angiotensin II stimulates the tyrosine phosphorylation of PDPK1 in vascular smooth muscle in a calcium- and SRC-dependent manner. Phosphorylated on Tyr-9, Tyr-373 and Tyr-376 by INSR in response to insulin. Palmitate negatively regulates autophosphorylation at Ser-241 and palmitate-induced phosphorylation at Ser-529 and Ser-501 by PKC/PRKCQ negatively regulates its ability to phosphorylate PKB/AKT1. Phosphorylation at Thr-354 by MELK partially inhibits kinase activity, the inhibition is cooperatively enhanced by phosphorylation at Ser-394 and Ser-398 by MAP3K5.PTM Autophosphorylated; autophosphorylation is inhibited by the apoptotic C-terminus cleavage product of PKN2.PTM Monoubiquitinated in the kinase domain, deubiquitinated by USP4.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PDPK1 subfamily.

UniProtO15530

EQUAL

556

EQUAL

Reactome DB_ID: 377179

PDPK1:PIP3 [plasma membrane]

PDPK1:PIP3

PDK1:PIP3

Reactome DB_ID: 179838

Reactome DB_ID: 61459

EQUAL

556

EQUAL

Reactome Database ID Release 70377179Database 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=377179ReactomeR-HSA-377179

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-377179.1Reactome Database ID Release 702316429Database 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=2316429ReactomeR-HSA-2316429

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-2316429.39895304Pubmed1999Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1Currie, RAWalker, KSGray, ADeak, MCasamayor, ADownes, CPCohen, PAlessi, DRLucocq, JBiochem J 337:575-83

PIP3 recruits AKT to the membrane

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.

Reactome DB_ID: 179838

Converted from EntitySet in Reactome

Reactome DB_ID: 202088

AKT [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityAKT1 [cytosol]

UniProtP31749

Reactome DB_ID: 2317329

AKT:PIP3 [plasma membrane]

AKT:PIP3

Reactome DB_ID: 179838

Converted from EntitySet in Reactome

Reactome DB_ID: 202052

AKT [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityAKT1 [plasma membrane]

Reactome Database ID Release 702317329Database 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=2317329ReactomeR-HSA-2317329

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-2317329.1Reactome Database ID Release 702317332Database 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=2317332ReactomeR-HSA-2317332

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-2317332.617914025Pubmed2008The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activationYin, HStojanovic, AHay, NDu, XBlood 111:658-6512167717Pubmed2002Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase BScheid, MPMarignani, PAWoodgett, JRMol Cell Biol 22:6247-602008The role of Akt3 in Platelet ActivationO'Brien, KStojanovic, AHay, NDu, XArteriosclerosis, Thrombosis, and Vascular Biology 28:e162GO0032148

GO biological process

2.7.11

TORC2 (mTOR) phosphorylates AKT at S473

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).

Reactome DB_ID: 2317329

Reactome DB_ID: 113592

Reactome DB_ID: 2317310

p-S-AKT:PIP3 [plasma membrane]

p-S-AKT:PIP3

Reactome DB_ID: 179838

Converted from EntitySet in Reactome

Reactome DB_ID: 2317317

p-S-AKT [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-S473-AKT1 [plasma membrane]

Reactome Database ID Release 702317310Database 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=2317310ReactomeR-HSA-2317310

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-2317310.1

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 198626

TORC2 complex [cytosol]

TORC2 complex

mTORC2mTOR2

Reactome DB_ID: 3006620

UniProt:Q9BPZ7 MAPKAP1

MAPKAP1

MAPKAP1MIP1SIN1FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription. Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex.SUBUNIT All isoforms except isoform 4 can be incorporated into the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts with ATF2, MAP3K2 and MAPK8. Interacts with GTP-bound HRAS and KRAS. Interacts with IFNAR2 and SGK1. Isoform 2 interacts with NBN. Isoform 1 interacts with CCDC28B.TISSUE SPECIFICITY Ubiquitously expressed, with highest levels in heart and skeletal muscle.SIMILARITY Belongs to the SIN1 family.

UniProtQ9BPZ7

EQUAL

522

EQUAL

Reactome DB_ID: 165676

UniProt:Q9BVC4 MLST8

MLST8

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

UniProtQ9BVC4

EQUAL

326

EQUAL

Reactome DB_ID: 198632

UniProt:Q6R327 RICTOR

RICTOR

KIAA1999RICTORFUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Plays an essential role in embryonic growth and development.SUBUNIT Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR (PubMed:15268862, PubMed:15467718, PubMed:17461779, PubMed:17599906). Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and PRR5 within the TORC2 complex (PubMed:15268862, PubMed:17461779, PubMed:17599906). Interacts with CCDC28B (PubMed:23727834). Interacts with NBN (PubMed:23762398). Interacts with PRR5L (PubMed:17461779, PubMed:21964062). Interacts with SIK3 (PubMed:30232230).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.PTM Phosphorylated by MTOR; when part of mTORC2. Phosphorylated at Thr-1135 by RPS6KB1; phosphorylation of RICTOR inhibits mTORC2 and AKT1 signaling.SIMILARITY Belongs to the RICTOR family.

UniProtQ6R327

EQUAL

1708

EQUAL

Reactome DB_ID: 165662

UniProt:P42345 MTOR

MTOR

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

UniProtP42345

EQUAL

2549

EQUAL

Reactome DB_ID: 6795323

UniProt:P85299 PRR5

PRR5

PRR5PROTOR1PP610FUNCTION Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. PRR5 plays an important role in regulation of PDGFRB expression and in modulation of platelet-derived growth factor signaling. May act as a tumor suppressor in breast cancer.SUBUNIT Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Binds directly to MTOR and RICTOR within the TORC2 complex.TISSUE SPECIFICITY Most abundant in kidney and liver. Also highly expressed in brain, spleen, testis and placenta. Overexpressed in several colorectal tumors.SIMILARITY Belongs to the PROTOR family.

UniProtP85299

EQUAL

388

EQUAL

Reactome Database ID Release 70198626Database 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=198626ReactomeR-HSA-198626

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-198626.2GO0004674

GO molecular function

Reactome Database ID Release 70198624Database 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=198624Reactome Database ID Release 70198640Database 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=198640ReactomeR-HSA-198640

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-198640.415718470Pubmed2005Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complexSarbassov, DDGuertin, DAAli, SMSabatini, DMScience 307:1098-10115314020Pubmed2004Upstream and downstream of mTORHay, NSonenberg, NahumGenes Dev 18:1926-4515268862Pubmed2004Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeletonSarbassov, DDAli, SMKim, DHGuertin, DALatek, RRErdjument-Bromage, HTempst, PSabatini, DMCurr Biol 14:1296-30219303758Pubmed2009PIKKing on PKB: regulation of PKB activity by phosphorylationBozulic, LHemmings, BACurr Opin Cell Biol 21:256-6115467718Pubmed2004Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitiveJacinto, ELoewith, RSchmidt, ALin, SRuegg, MAHall, AHall, MNNat Cell Biol 6:1122-8

INHIBITION

Reactome Database ID Release 70199457Database 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=199457ReactomeR-HSA-199457

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-199457.2

Reactome DB_ID: 199453

AKT:PIP3:THEM4/TRIB3 [plasma membrane]

AKT:PIP3:THEM4/TRIB3

Reactome DB_ID: 2317329

Converted from EntitySet in Reactome

Reactome DB_ID: 2400007

THEM4/TRIB3 [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTHEM4 [plasma membrane]TRIB3 [plasma membrane]

UniProtQ5T1C6UniProtQ96RU7Reactome Database ID Release 70199453Database 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=199453ReactomeR-HSA-199453

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-199453.1

AKT binds PDPK1

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)

Authored: Orlic-Milacic, M, 2012-07-18Reviewed: Thorpe, Lauren, 2012-08-13Reviewed: Yuzugullu, Haluk, 2012-08-13Reviewed: Zhao, Jean J, 2012-08-13Edited: Matthews, L, 2012-08-03

Reactome DB_ID: 2317310

Reactome DB_ID: 377179

Reactome DB_ID: 2317313

p-S-AKT:PDPK1:PIP3 [plasma membrane]

p-S-AKT:PDPK1:PIP3

Reactome DB_ID: 2317310

Reactome DB_ID: 377179

Reactome Database ID Release 702317313Database 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=2317313ReactomeR-HSA-2317313

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-2317313.1Reactome Database ID Release 702317314Database 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=2317314ReactomeR-HSA-2317314

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-2317314.3

2.7.11

PDPK1 phosphorylates AKT at T308

Once AKT is localized at the plasma membrane, it is phosphorylated at two critical residues for its full activation. These residues are a threonine (T308 in AKT1) in the activation loop within the catalytic domain, and a serine (S473 in AKT1), in a hydrophobic motif (HM) within the carboxy terminal, non-catalytic region. PDPK1 (PDK1) is the activation loop kinase; this kinase can also directly phosphorylate p70S6K. The HM kinase, previously termed PDK2, has been identified as the mammalian TOR (Target Of Rapamycin; Sarbassov et al., 2005) but several other kinases are also able to phosphorylate AKT at S473. Phosphorylation of AKT at S473 by TORC2 complex is a prerequisite for PDPK1-mediated phosphorylation of AKT threonine T308 (Scheid et al. 2002, Sarabassov et al. 2005).

Reactome DB_ID: 2317313

Reactome DB_ID: 113592

Converted from EntitySet in Reactome

Reactome DB_ID: 202074

p-T,p-S-AKT [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-T308,S473-AKT1 [cytosol]

Reactome DB_ID: 29370

Reactome DB_ID: 377179

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2317313

Reactome Database ID Release 70198343Database 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=198343Reactome Database ID Release 70198270Database 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=198270ReactomeR-HSA-198270

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-198270.27637810Pubmed1995Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transductionBurgering, BMCoffer, PJNature 376:599-6029736715Pubmed1998Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinaseDelcommenne, MTan, CGray, VRue, LWoodgett, JDedhar, SProc Natl Acad Sci U S A 95:11211-6

2.7.11

AKT interacts and phosphorylates Cot

Cot/Tpl 2 is a serine/threonine kinase of the mitogen activated protein kinase kinase kinase (MAP3K) family. Cot is observed as one of the downstream effectors of Akt. Based on in-vitro kinase assays and following overexpression in cell lines its been showed that AKT can phosphorylate Cot under non-physiological conditions. Akt and Cot physically interact through the amino terminus of Cot, and this interaction results in the phosphorylation of Cot on serine 400. Cot was shown to activate the IkB kinase (IKK) complex, possibly acting through NF kB inducing kinase (NIK).

Authored: Garapati, P V, 2008-12-16 11:12:19Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33Edited: Garapati, P V, 2008-12-16 11:12:19

Reactome DB_ID: 113592

Reactome DB_ID: 389388

UniProt:P41279 MAP3K8

MAP3K8

ESTFCOTMAP3K8FUNCTION Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.SUBUNIT Forms a ternary complex with NFKB1/p105 and TNIP2. Interacts with NFKB1; the interaction increases the stability of MAP3K8 but inhibits its MEK phosphorylation activity, whereas loss of interaction following LPS stimulation leads to its degradation. Interacts with CD40 and TRAF6; the interaction is required for ERK activation. Interacts with KSR2; the interaction inhibits ERK and NF-kappa-B activation.TISSUE SPECIFICITY Expressed in several normal tissues and human tumor-derived cell lines.DEVELOPMENTAL STAGE Isoform 1 is activated specifically during the S and G2/M phases of the cell cycle.INDUCTION Up-regulated by IL12 in T-lymphocytes. Up-regulated in subcutaneous adipose tissue of obese individuals.PTM Autophosphorylated (PubMed:8226782, PubMed:1833717). Isoform 1 undergoes phosphorylation mainly on Ser residues, and isoform 2 on both Ser and Thr residues (PubMed:8226782). Phosphorylated on Thr-290; the phosphorylation is necessary but not sufficient for full kinase activity in vitro and for the dissociation of isoform 1 from NFKB1, leading to its degradation (PubMed:15466476, PubMed:15699325). Phosphorylated on Ser-400 by IKBKB; the phosphorylation is required for LPS-stimulated activation of the MAPK/ERK pathway in macrophages (PubMed:17472361, PubMed:22988300).MISCELLANEOUS Can be converted to an oncogenic protein by proviral activation, leading to a C-terminally truncated protein with transforming activity.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.CAUTION A paper describing a role for this protein in IRAK1-independent activation of the MAPK/ERK pathway in response to IL1 has been retracted, because some of the experimental data could not be reproduced.

UniProtP41279

EQUAL

467

EQUAL

Reactome DB_ID: 29370

Reactome DB_ID: 389738

O-phospho-L-serine at 400

400

EQUAL

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

EQUAL

467

EQUAL

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 202074

Reactome Database ID Release 70198368Database 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=198368Reactome Database ID Release 70389756Database 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=389756ReactomeR-HSA-389756

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-389756.212138205Pubmed2002Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcriptionKane, LPMollenauer, MNXu, ZTurck, CWWeiss, AMol Cell Biol 22:5962-74

2.7.11.25

p-S400-Cot phosphorylates NIK

Cot functions upstream of NIK in the CD28-costimulation signaling pathway leading to activation of NF-kB. Cot binds avidly to NIK and induces NIK phosphorylation in vivo.

Authored: Garapati, P V, 2008-12-16 11:12:19Reviewed: Bluestone, JA, Esensten, J, 2009-06-01 18:47:33Edited: Garapati, P V, 2008-12-16 11:12:19

Reactome DB_ID: 113592

Reactome DB_ID: 168189

UniProt:Q99558 MAP3K14

MAP3K14

NIKMAP3K14FUNCTION Lymphotoxin beta-activated kinase which seems to be exclusively involved in the activation of NF-kappa-B and its transcriptional activity. Promotes proteolytic processing of NFKB2/P100, which leads to activation of NF-kappa-B via the non-canonical pathway. Could act in a receptor-selective manner.SUBUNIT Interacts with TRAF2, TRAF5, TRAF6, IKKA and NFKB2/P100 (By similarity). Interacts with TRAF3 and PELI3. Interacts with NIBP; the interaction is direct. Interacts with ARRB1 and ARRB2. Interacts with GRB10. Interacts with ZFP91. Interacts with NLRP12; this interaction promotes proteasomal degradation of MAP3K14.TISSUE SPECIFICITY Weakly expressed in testis, small intestine, spleen, thymus, peripheral blood leukocytes, prostate, ovary and colon.PTM Autophosphorylated. Phosphorylation at Thr-559 is required to activates its kinase activity and 'Lys-63'-linked polyubiquitination. Phosphorylated by CHUK/IKKA leading to MAP3K14 destabilization.PTM Ubiquitinated. Undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. 'Lys-48'-linked polyubiquitination leads to its degradation by the proteasome, while 'Lys-63'-linked polyubiquitination stabilizes and activates it.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

UniProtQ99558

EQUAL

947

EQUAL

Reactome DB_ID: 168187

phosphorylated residue at unknown position

phosphorylated residue [MOD:00696]

EQUAL

947

EQUAL

Reactome DB_ID: 29370

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 389738

O-phospho-L-serine at 400

400

EQUAL

467

EQUAL

GO0004709

GO molecular function

Reactome Database ID Release 70392534Database 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=392534Reactome Database ID Release 70392530Database 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=392530ReactomeR-HSA-392530

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-392530.118439422Pubmed2008NIK and Cot cooperate to trigger NF-kappaB p65 phosphorylationWittwer, TSchmitz, MLBiochem Biophys Res Commun 371:294-7

Reactome Database ID Release 70389357Database 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=389357ReactomeR-HSA-389357

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-389357.115046602Pubmed2004Phosphoinositide 3-kinase in T cell activation and survivalOkkenhaug, KBilancio, AEmery, JLVanhaesebroeck, BBiochem Soc Trans 32:332-5