PI3K-Akt Signaling
The PI3K/Akt pathway is pivotal for cellular homeostasis, neurological development, metabolism, and other processes. It regulates various aspects of cellular development such as apoptosis, cell cycle progression, and cell differentiation.
The key regulator of the PI3K/Akt pathway is Akt/PKB, a family of three closely related serine/threonine-protein kinases. Akt1/PKB alpha plays an important role in cell proliferation and cell metabolism. Akt2/PKB beta is of great significance for glucose metabolism. Akt3/PKB gamma is the least characterized member of the Akt family but it is mainly expressed in the brain where it is thought to regulate mitochondrial biogenesis.
Mutations in Akt contribute oftentimes to deregulation of these processes and the emergence of various forms of cancer. Akt hyperactivation also leads to increased glycolysis, thus supporting the metabolic transformation of cancer cells. Akt has been implicated in the development of cancer drug resistance and is therefore subject of preclinical and clinical research. However, Akt activation alone is usually not sufficient and other mutations are generally necessary to create the cancer phenotype.
Loss of function of the major Akt regulators PI3K and PTEN can lead to hyperactivation of Akt. PI3Ks are an enzyme family that phosphorylate PtdIns (Phosphatidylinositol) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). Upon activation by receptor tyrosine kinase PI3K phosphorylates PIP2 to PIP3 which then activates Akt signaling. PTEN acts as a negative regulator of the signal transduction by dephosphorylation of PIP3 to PIP2.
Akt
AKT1 - AKT
The serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through...
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AKT2 (V-Akt Murine Thymoma Viral Oncogene Homolog 2):
AKT3 (V-Akt Murine Thymoma Viral Oncogene Homolog 3 (Protein Kinase B, Gamma)):
AMPA receptors
GRIA1 (Glutamate Receptor, Ionotropic, AMPA 1):
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their...
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GRIA2 (Glutamate Receptor, Ionotropic, AMPA 2):
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and function as ligand-activated cation channels. These channels are assembled...
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GRIA3 - Glutamate Receptor 3:
GRIA4 (Glutamate Receptor, Ionotropic, AMPA 4):
Apoptosis
BCL2 (B-Cell CLL/lymphoma 2):
This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Two transcript variants, produced by alternate splicing, differ in their C-terminal ends. [provided by...
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MDM2 (Mdm2, p53 E3 Ubiquitin Protein Ligase Homolog (Mouse)):
This gene is a target gene of the transcription factor tumor protein p53. The encoded protein is a nuclear phosphoprotein that binds and inhibits transactivation by tumor protein p53, as part of an autoregulatory negative feedback loop. Overexpression of this gene can result in excessive inactivation of tumor protein p53, diminishing its tumor suppressor function. This protein has E3 ubiquitin...
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BAD (BCL2-Associated Agonist of Cell Death):
BAX (BCL2-Associated X Protein):
BCL2L11 - BIM:
FOXO1 (Forkhead Box O1):
Cell cycle
CCNA2 - Cyclin A
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. In contrast to cyclin A1,...
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CDKN1A (Cyclin-Dependent Kinase Inhibitor 1A (p21, Cip1)):
This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and thus functions as a regulator of cell cycle progression at G1. The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G1 phase arrest in...
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CCND1 - Cyclin D1:
CDK2 (Cyclin-Dependent Kinase 2):
CDK2AP2 (Cyclin-Dependent Kinase 2 Associated Protein 2):
GSK3a - GSK3 alpha:
Cell survival
EIF4EBP1 (Eukaryotic Translation Initiation Factor 4E Binding Protein 1):
This gene encodes one member of a family of translation repressor proteins. The protein directly interacts with eukaryotic translation initiation factor 4E (eIF4E), which is a limiting component of the multisubunit complex that recruits 40S ribosomal subunits to the 5' end of mRNAs. Interaction of this protein with eIF4E inhibits complex assembly and represses translation. This protein is...
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RPS6KB1 (Ribosomal Protein S6 Kinase, 70kDa, Polypeptide 1):
This gene encodes a member of the ribosomal S6 kinase family of serine/threonine kinases. The encoded protein responds to mTOR (mammalian target of rapamycin) signaling to promote protein synthesis, cell growth, and cell proliferation. Activity of this gene has been associated with human cancer. Alternatively spliced transcript variants have been observed. The use of alternative translation...
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ATG13 (Autophagy Related 13):
RPS6KB2 (Ribosomal Protein S6 Kinase, 70kDa, Polypeptide 2):
Glucose metabolism
GYS1 - Glycogen Synthase 1
The protein encoded by this gene catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages. Mutations in this gene are associated with muscle glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009].
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PIP5K1B (Phosphatidylinositol-4-Phosphate 5-Kinase, Type I, beta):
Participates in the biosynthesis of phosphatidylinositol 4,5-bisphosphate. Mediates RAC1-dependent reorganization of actin filaments. Contributes to the activation of PLD2. Together with PIP5K1A is required after stimulation of G-protein coupled receptors for stable platelet adhesion (By similarity).
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PFKFB2 (6-phosphofructo-2-Kinase/fructose-2,6-Biphosphatase 2):
GSK3a - GSK3 alpha:
HK2 - Hexokinase 2:
PIP5K1A (Phosphatidylinositol-4-Phosphate 5-Kinase, Type I, alpha):
PIP5K1C (Phosphatidylinositol-4-Phosphate 5-Kinase, Type I, gamma):
Immune response
GSK3a - GSK3 alpha
This gene encodes a multifunctional Ser/Thr protein kinase that is implicated in the control of several regulatory proteins including glycogen synthase, and transcription factors, such as JUN. It also plays a role in the WNT and PI3K signaling pathways, as well as regulates the production of beta-amyloid peptides associated with Alzheimer's disease. [provided by RefSeq, Oct 2011].
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NCF1 (Neutrophil Cytosol Factor 1):
The protein encoded by this gene is a 47 kDa cytosolic subunit of neutrophil NADPH oxidase. This oxidase is a multicomponent enzyme that is activated to produce superoxide anion. Mutations in this gene have been associated with chronic granulomatous disease. [provided by RefSeq, Jul 2008].
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CHUK (conserved Helix-Loop-Helix Ubiquitous Kinase):
MAP3K8 (Mitogen-Activated Protein Kinase Kinase Kinase 8):
mTORC1
MLST8 (mTOR Associated Protein, LST8 Homolog (S. Cerevisiae)):
cytosolic protein similar to an insulin receptor [RGD, Feb 2006].
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RPTOR - Raptor
This gene encodes a component of a signaling pathway that regulates cell growth in response to nutrient and insulin levels. The encoded protein forms a stoichiometric complex with the mTOR kinase, and also associates with eukaryotic initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase. The protein positively regulates the downstream effector ribosomal protein S6 kinase, and...
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DEPTOR (DEP Domain Containing mTOR-Interacting Protein):
mTORC2
DEPTOR (DEP Domain Containing mTOR-Interacting Protein):
Negative regulator of the mTORC1 and mTORC2 signaling pathways. Inhibits the kinase activity of both complexes (By similarity).
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TNPO1 - Transportin 1
This gene encodes the beta subunit of the karyopherin receptor complex which interacts with nuclear localization signals to target nuclear proteins to the nucleus. The karyopherin receptor complex is a heterodimer of an alpha subunit which recognizes the nuclear localization signal and a beta subunit which docks the complex at nucleoporins. Alternate splicing of this gene results in two...
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mTOR - MTOR:
MAPKAP1 (Mitogen-Activated Protein Kinase Associated Protein 1):
MLST8 (mTOR Associated Protein, LST8 Homolog (S. Cerevisiae)):
PRR5 - Proline Rich 5 (Renal):
Neural development
HTT - Huntingtin
Huntingtin is a disease gene linked to Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range in the number of trinucleotide repeats has been identified in normal...
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PDK
PDPK1 (3-phosphoinositide Dependent Protein Kinase-1):
Serine/threonine kinase required for embryonic development. Inhibits apoptosis. Acts in the insulin receptor transduction pathway which regulates cell growth and organ size, by phosphorylating and activating Akt1 and S6k. May be involved in axonal pathfinding and synaptogenesis, and in spermatogenesis.
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PDK1 (Pyruvate Dehydrogenase Kinase, Isozyme 1):
Pyruvate dehydrogenase (PDH) is a mitochondrial multienzyme complex that catalyzes the oxidative decarboxylation of pyruvate and is one of the major enzymes responsible for the regulation of homeostasis of carbohydrate fuels in mammals. The enzymatic activity is regulated by a phosphorylation/dephosphorylation cycle. Phosphorylation of PDH by a specific pyruvate dehydrogenase kinase (PDK)...
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PDK2 (Pyruvate Dehydrogenase Kinase, Isozyme 2):
PDK3 (Pyruvate Dehydrogenase Kinase, Isozyme 3):
PDK4 (Pyruvate Dehydrogenase Kinase, Isozyme 4):
PHLPP
PHLPP1 (PH Domain and Leucine Rich Repeat Protein Phosphatase 1):
This gene encodes a member of the serine/threonine phosphatase family. The encoded protein promotes apoptosis by dephosphorylating and inactivating the serine/threonine kinase Akt, and functions as a tumor suppressor in multiple types of cancer. Increased expression of this gene may also play a role in obesity and type 2 diabetes by interfering with Akt-mediated insulin signaling. [provided by...
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PHLPP2 (PH Domain and Leucine Rich Repeat Protein Phosphatase 2):
PI3K
PIK3CA (Phosphoinositide-3-Kinase, Catalytic, alpha Polypeptide):
Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. [provided by RefSeq, Jul 2008].
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PIK3R5 (Phosphoinositide-3-Kinase, Regulatory Subunit 5):
Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the inositol ring of phosphatidylinositol at the 3-prime position, and play important roles in cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PI3Ks are divided into three classes: I, II and III, and only the class I PI3Ks are involved in oncogenesis. This gene encodes the 101 kD regulatory...
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PIK3CG (Phosphoinositide-3-Kinase, Catalytic, gamma Polypeptide):
PIK3R6 (Phosphoinositide-3-Kinase, Regulatory Subunit 6):
PIK3R5 (Phosphoinositide-3-Kinase, Regulatory Subunit 5):
PP2A
PPP2CA - Protein Phosphatase 2, Catalytic Subunit, alpha Isozyme
This gene encodes the phosphatase 2A catalytic subunit. Protein phosphatase 2A is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. This gene encodes...
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PPP2R4 (Protein Phosphatase 2A Activator, Regulatory Subunit 4):
Protein phosphatase 2A is one of the four major Ser/Thr phosphatases and is implicated in the negative control of cell growth and division. Protein phosphatase 2A holoenzymes are heterotrimeric proteins composed of a structural subunit A, a catalytic subunit C, and a regulatory subunit B. The regulatory subunit is encoded by a diverse set of genes that have been grouped into the B/PR55,...
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MTS - Microtubule Star:
PPP2R1A (Protein Phosphatase 2, Regulatory Subunit A, alpha):
PPP2R1B (Protein Phosphatase 2, Regulatory Subunit A, beta):
PPP2R3A (Protein Phosphatase 2, Regulatory Subunit B'', alpha):
PPP2R3C (Protein Phosphatase 2, Regulatory Subunit B'', gamma):
PPP2R5A (Protein Phosphatase 2, Regulatory Subunit B', alpha):
PPP2R5B (Protein Phosphatase 2, Regulatory Subunit B', beta):
PPP2R5D (Protein Phosphatase 2, Regulatory Subunit B', delta):
PPP2R5E (Protein Phosphatase 2, Regulatory Subunit B', epsilon Isoform):
PPP2CA - Protein Phosphatase 2, Regulatory Subunit B', gamma:
PPP2R2B (Protein Phosphatase 2, Regulatory Subunit B, beta):
PPP2R2C (Protein Phosphatase 2, Regulatory Subunit B, gamma):
PPP2R3B (Protein Phosphatase 2A 48 KDa Regulatory Subunit):
Others
HBXIP (Hepatitis B Virus X-Interacting Protein):
This gene encodes a protein that specifically complexes with the C-terminus of hepatitis B virus X protein (HBx). The function of this protein is to negatively regulate HBx activity and thus to alter the replication life cycle of the virus. [provided by RefSeq, Jul 2008].
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LAMTOR2 (Late Endosomal/lysosomal Adaptor, MAPK and mTOR Activator 2):
The product of this gene is highly conserved with a mouse protein associated with the cytoplasmic face of late endosomes and lysosomes. The mouse protein interacts with MAPK scaffold protein 1, a component of the mitogen-activated protein kinase pathway. In humans, a mutation in this gene has been associated with a primary immunodeficiency syndrome, and suggests a role for this protein in...
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MAPKSP1 (Mitogen-Activated Protein Kinase Kinase 1 Interacting Protein 1):
PITRM1 (Pitrilysin Metallopeptidase 1):
PPP1R2 (Protein Phosphatase 1, Regulatory (Inhibitor) Subunit 2):
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