Search results for AKT2

Showing 19 results out of 30

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Protein (5 results from a total of 7)

Identifier: R-HSA-202053
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: AKT2: P31751
Identifier: R-HSA-49859
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: AKT2: P31751
Identifier: R-HSA-2317312
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: AKT2: P31751
Identifier: R-HSA-202066
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: AKT2: P31751
Identifier: R-HSA-202062
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: AKT2: P31751

Pathway (3 results from a total of 3)

Identifier: R-HSA-165158
Species: Homo sapiens
RAC serine/threonine-protein kinases (AKT, PKB) are serine/threonine kinases belonging to the cAMP-dependent protein kinase A/ protein kinase G/ protein kinase C (AGC) superfamily of protein kinases. They share structural homology within their catalytic domains and have similar mechanisms of activation. Mammals have three AKT genes, named RAC-alpha serine/threonine-protein kinase (AKT1, PKB, PKB-alpha), RAC-beta serine/threonine-protein kinase (AKT2, PKB-beta and RAC-gamma serine/threonine-protein kinase (AKT3, PKB-gamma, STK2). All share a conserved domain structure: an amino terminal pleckstrin homology (PH) domain, a central kinase domain and a carboxyl-terminal regulatory domain that contains a hydrophobic motif that is characteristic of AGC kinases. The PH domain interacts with membrane lipid products such as phosphatidylinositol (3,4,5) trisphosphate (PIP3) produced by phosphatidylinositol 3-kinase (PI3-kinase). Biochemical analysis. The PH domain of AKT binds to PIP3 and PIP2 with similar affinity (James et al. 1996, Frech et al. 1997). The kinase catalytic domain of Akt/PKB is highly similar to other AGC kinases (Peterson & Schreiber 1999). Phosphorylation of a conserved threonine residue in this region (T308 in AKT1) results in partial activation (Alessi et al. 1996). The carboxyl terminal extension has the hydrophobic motif FPQFSY. Phosphorylation of serine or threonine residue in this motif is necessary for full kinase activation. Deletion of this motif completely abolishes activity (Andjelković et al. 1997).
Identifier: R-HSA-1445148
Species: Homo sapiens
Compartment: cytoplasmic vesicle membrane, cytosol
In adipocytes and myocytes insulin signaling causes intracellular vesicles carrying the GLUT4 (SLC2A4) glucose transporter to translocate to the plasma membrane, allowing the cells to take up glucose from the bloodstream (reviewed in Zaid et al. 2008, Leney and Tavare 2009, Bogan and Kandror 2010, Foley et al. 2011, Hoffman and Elmendorf 2011, Kandror and Pilch 2011, Jaldin-Fincati et al. 2017). In myocytes muscle contraction alone can also cause translocation of GLUT4.
Though the entire pathway leading to GLUT4 translocation has not been elucidated, several steps are known. Insulin activates the kinases AKT1 and AKT2. Muscle contraction activates the kinase AMPK-alpha2 and possibly also AKT. AKT2 and, to a lesser extent, AKT1 phosphorylate the RAB GTPase activators TBC1D1 and TBC1D4, causing them to bind 14-3-3 proteins and lose GTPase activation activity. As a result RAB proteins (probably RAB8A, RAB10, RAB14 and possibly RAB13) accumulate GTP. The connection between RAB:GTP and vesicle translocation is unknown but may involve recruitment and activation of myosins.
Myosins 1C, 2A, 2B, 5A, 5B have all been shown to play a role in translocating GLUT4 vesicles near the periphery of the cell. Following docking at the plasma membrane the vesicles fuse with the plasma membrane in a process that depends on interaction between VAMP2 on the vesicle and SNAP23 and SYNTAXIN-4 at the plasma membrane.
Identifier: R-HSA-2219528
Species: Homo sapiens
Class IA PI3K is a heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). In the absence of activating signals, the regulatory subunit stabilizes the catalytic subunit while inhibiting its activity. The complex becomes activated when extracellular signals stimulate the phosphorylation of the cytoplasmic domains of transmembrane receptors or receptor-associated proteins. The p85 regulatory subunit binds phosphorylated motifs of activator proteins, which induces a conformational change that relieves p85-mediated inhibition of the p110 catalytic subunit and enables PI3K to phosphorylate PIP2 to form PIP3. The phosphoinositide kinase activity of PI3K is opposed by the phosphoinositide phosphatase activity of PTEN.

PIP3 acts as a messenger that recruits PDPK1 (PDK1) and AKT (AKT1, AKT2 or AKT3) to the plasma membrane. PDPK1 also possesses a low affinity for PIP2, so small amounts of PDPK1 are always present at the membrane. Binding of AKT to PIP3 induces a conformational change that enables TORC2 complex to phosphorylate AKT at a conserved serine residue (S473 in AKT1). Phosphorylation at the serine residue enables AKT to bind to PDPK1 and exposes a conserved threonine residue (T308) that is phosphorylated by PDPK1. AKT phosphorylated at both serine and threonine residues dissociates from the plasma membrane and acts as a serine/threonine kinase that phosphorylates a number of cytosolic and nuclear targets involved in regulation of cell metabolism, survival and gene expression. For a recent review, please refer to Manning and Cantley, 2007.
Signaling by PI3K/AKT is frequently constitutively activated in cancer. This activation can be via gain-of-function mutations in PI3KCA (encoding catalytic subunit p110alpha), PIK3R1 (encoding regulatory subunit p85alpha) and AKT1. The PI3K/AKT pathway can also be constitutively activated by loss-of-function mutations in tumor suppressor genes such as PTEN.
Gain-of-function mutations activate PI3K signaling by diverse mechanisms. Mutations affecting the helical domain of PIK3CA and mutations affecting nSH2 and iSH2 domains of PIK3R1 impair inhibitory interactions between these two subunits while preserving their association. Mutations in the catalytic domain of PIK3CA enable the kinase to achieve an active conformation. PI3K complexes with gain-of-function mutations therefore produce PIP3 and activate downstream AKT in the absence of growth factors (Huang et al. 2007, Zhao et al. 2005, Miled et al. 2007, Horn et al. 2008, Sun et al. 2010, Jaiswal et al. 2009, Zhao and Vogt 2010, Urick et al. 2011). While AKT1 gene copy number, expression level and phosphorylation are often increased in cancer, only one low frequency point mutation has been repeatedly reported in cancer and functionally studied. This mutation represents a substitution of a glutamic acid residue with lysine at position 17 of AKT1, and acts by enabling AKT1 to bind PIP2. PIP2-bound AKT1 is phosphorylated by TORC2 complex and by PDPK1 that is always present at the plasma membrane, due to low affinity for PIP2. Therefore, E17K substitution abrogates the need for PI3K in AKT1 activation (Carpten et al. 2007, Landgraf et al. 2008).
Loss-of-function mutations affecting the phosphatase domain of PTEN are frequently found in sporadic cancers (Kong et al. 1997, Lee et al. 1999, Han et al. 2000), as well as in PTEN hamartoma tumor syndromes (PHTS) (Marsh et al. 1998). PTEN can also be inactivated by gene deletion or epigenetic silencing, or indirectly by overexpression of microRNAs that target PTEN mRNA (Huse et al. 2009). Cells with deficient PTEN function have increased levels of PIP3, and therefore increased AKT activity. For a recent review, please refer to Hollander et al. 2011.
Because of their clear involvement in human cancers, PI3K and AKT are targets of considerable interest in the development of small molecule inhibitors. Although none of the currently available inhibitors display preference for mutant variants of PIK3CA or AKT, several inhibitors targeting the wild-type kinases are undergoing clinical trials. These include dual PI3K/mTOR inhibitors, class I PI3K inhibitors, pan-PI3K inhibitors, and pan-AKT inhibitors. While none have yet been approved for clinical use, these agents show promise for future therapeutics. In addition, isoform-specific PI3K and AKT inhibitors are currently being developed, and may provide more specific treatments along with reduced side-effects. For a recent review, please refer to Liu et al. 2009.

Reaction (5 results from a total of 14)

Identifier: R-HSA-109702
Species: Homo sapiens
Compartment: cytosol, plasma membrane
Two specific sites in AKT2, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation.
Identifier: R-HSA-109700
Species: Homo sapiens
Compartment: plasma membrane, cytosol
The phosphorylation of membrane-recruited AKT at threonine and serine can be inhibited by direct binding of two different proteins, C-terminal modulator protein (THEM4 i.e. CTMP), which binds to the carboxy-terminal tail of AKT (Maira et al. 2001), or Tribbles homolog 3 (TRIB3), which binds to the catalytic domain of AKT (Du et al. 2003).
Identifier: R-HSA-1458463
Species: Homo sapiens
Compartment: cytosol, plasma membrane
As inferred from mouse, AKT2 (PKB-beta) phosphorylates RBC2 (RALGAPA2) on serine-486, serine-696, and threonine-715 in response to insulin. The phosphorylation prevents RBC1:RBC2 from activating RALA GTPase and allows RALA:GTP to accumulate.
Identifier: R-HSA-5260201
Species: Homo sapiens
Compartment: cytosol, plasma membrane
The protein kinase B beta (AKT) pathway mediates insulin-stimulated glucose transport by increasing glucose transporter GLUT4 translocation from intracellular stores to the plasma membrane. C2 domain-containing protein 5 (C2CD5 aka C2 domain-containing phosphoprotein 138kDa) has been shown to be required for optimal insulin-stimulated GLUT4 translocation and fusion of GLUT4 vesicles with the plasma membrane in adipocytes. It is also able to bind Ca2+ and lipid membranes in its C2 domain. C2CD5 is a substrate for RAC-beta serine/threonine-protein kinase (AKT2), which phosphorylates C2CD5 at serine 197. Phosphorylated C2CD5 optimises GLUT4 translocation to the plasma membrane. The role of human C2CD5 is inferred from the role of the orthologous mouse protein (Xie et al. 2011).
Identifier: R-HSA-1449597
Species: Homo sapiens
Compartment: cytosol, plasma membrane
As inferred from mouse, AKT2 phosphorylates Myosin 5A on serine-1652. The phosphorylation promotes association of Myosin 5A with actin and ATPase activity of Myosin 5A.

Set (2 results from a total of 2)

Identifier: R-HSA-9023954
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-202072
Species: Homo sapiens
Compartment: nucleoplasm

Complex (3 results from a total of 3)

Identifier: R-HSA-109696
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-162401
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-162387
Species: Homo sapiens
Compartment: plasma membrane

Icon (1 results from a total of 1)

AKT

Species: Homo sapiens
Generic representation of AKT1, AKT2 and/or AKT3
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