AKT1

V-akt murine thymoma viral oncogene homolog 1 (AKT1), or protein kinase B-alpha (PKB-ALPHA) is a serine-threonine protein kinase, belonging to the Protein Kinase Superfamily. AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. AKT1 activity is required for physiologic cardiac growth in response to IGF1 stimulation or exercise training. In contrast, AKT1 activity was found to antagonize pathologic cardiac growth that occurs in response to endothelin 1 stimulation or pressure overload. AKT1 selectively promotes physiological cardiac growth while AKT2 selectively promotes insulin-stimulated cardiac glucose metabolism. AKT1 deletion prevented tumor initiation as well as tumor progression, coincident with decreased Akt signaling in tumor tissues.

AKT1 Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Akt/PKB>>AKT1

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Akt/PKB>>AKT1

AKT1 Related Pathways

• EGFR Signaling Pathway
• TGF-beta Signaling
• VEGF Signaling
• Cytokine Receptor Signaling

AKT1 Alternative Names

AKT1, AKT, PKB-ALPHA, PRKBA, MGC99656, PKB, RAC, RAC-ALPHA, RAC-PK-alpha [Homo sapiens]

Akt1, Akt, PKB, PKBalpha, PKB/Akt, Rac [Mus musculus]

Summaries for AKT1

Entrez Gene summary for AKT1:

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 phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mutations in this gene have been associated with the Proteus syndrome. Multiple alternatively spliced transcript variants have been found for AKT1 gene.

OMIM - description for AKT1:

Phosphoinositide 3-kinases, or PI3Ks (see PIK3CA; 171834), generate specific inositol lipids implicated in the regulation of cell growth, proliferation, survival, differentiation, and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase AKT, or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and by phosphorylation by 3-prime phosphoinositide-dependent kinase-1 (PDPK1; 605213). For a review of the mechanism that activates PKB and the downstream actions of this multifunctional kinase, see Vanhaesebroeck and Alessi (2000). For a review of the possible role of PKB in glucose transport, see Hajduch et al. (2001).

Wikipedia summary for AKT1:

RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for AKT1 gene.

Human AKT1 Protein General Information

 

• Protein names: RAC-alpha serine/threonine-protein kinase, Short namen=AKT1
• Sequence length: 480 AA.
• Domain: Binding of the PH domain to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction
• Sequence similarities: AKT1 belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily. Contains 1 AGC-kinase C-terminal domain. Contains 1 PH domain. Contains 1 protein kinase domain.
• Post-translational modification: Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity. Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA. This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation. Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1. Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells. Ser-473 phosphorylation is enhanced by signaling through activated FLT3. Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase. The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase.
• Subunit structure: Interacts with AGAP2 (isoform 2, PIKE-A), the interaction requires guanine nucleotides and stimulates the kinase activity. Interacts (via the C-terminus) with CCDC88A (via its C-terminus) and THEM4 (via its C-terminus). Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with MAP3K5 and TRAF6. Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE binding. Interacts with RARA; the interaction phosphorylates RARA and represses its transactivation activity. Interacts with TNK2. Interacts with CLK2 and PPP2R5B. Interacts with STK3/MST2 and STK4/MST1. Interacts (via PH domain) with SIRT1.
• Subcellular location: Cytoplasm. Nucleus. Cell membrane. Note: Nucleus after activation by integrin-linked protein kinase 1 (ILK1). Nuclear translocation is enhanced by interaction with TCL1A. Phosphorylation on Tyr-176 by TNK2 results in its localization to the cell membrane where it is targeted for further phosphorylations on Thr-308 and Ser-473 leading to its activation and the activated form translocates to the nucleus.
• Tissue specificity: Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.
• Involvement in disease: Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• Enzyme regulation: Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation. Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline.
• Caution: In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.
• Biophysicochemical properties: Kinetic parameters:
  KM=52.8 µM for ATP (for purified and in vitro activated AKT1) Ref.37
  KM=0.5 µM for peptide substrate (for purified and in vitro activated AKT1)
  KM=143.3 µM for ATP (for recombinant myristoylated AKT1 expressed and immunoprecipitated from Rat-1 cells)
  KM=2.9 µM for peptide substrate (for recombinant myristoylated AKT1 expressed and immunoprecipitated from Rat-1 cells)

General information above from UniProt

Function for AKT1 Protein

UniProtKB:

AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. AKT1 is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites.

Genatlas:

• AKT1 is a key regulator for cell growth, cell survival and metabolic insulin action
• AKT1 contributs to tumor-cell proliferation by phosphorylation and cytosolic retention of CDKN1B
• AKT1 is apoptotic regulator activated in many cancers
• AKT1 regulates the methylation activity, through phosphorylation of EZH2
• AKT1 inhibits chromatin condensation during apoptosis by phosphorylating ACIN1 in the nucleus, revealing a specific mechanism by which nuclear AKT1 promotes cell survival 
• AKT1 is able to transform keratinocytes by specific mechanisms involving transcriptional and post-transcriptional processes
• AKT1 is the key regulator of lamellipodia formation and cell motility
• AKT1 is involved in muscle differentiation through its involvement in PI3K signaling and is also involved in the regulation of MEF2A, MEF2B, MEF2C
• AKT1 with SLC9A1, has functions, including cell growth and survival, that might be regulated by increased H(+) efflux 
• isoforms of AKT1 regulate intermediate filament expression and intermediate filament are may be involved in PI3K/Akt pathway
• AKT1 is an important mediator of cardiac myocyte growth and survival
• primary Akt isoform activated by mutant KRAS in lung tumors

Homology for human AKT1

• homolog to C.elegans f28h6.1
• homolog to rattus Akt1 (98.12 pc)
• homolog to murine Akt1 (98.33 pc)

Phenotype Information for AKT1

• Gene/Locus: AKT1
• Phenotype: Breast cancer, somatic
  Colorectal cancer, somatic
  Ovarian cancer, somatic
  Proteus syndrome, somatic
  {Schizophrenia, susceptibility to}

Phenotype Information for AKT1 from OMIM (Online Mendelian Inheritance in Man)

Drugs for AKT1

Target	Drug Name	Disease	Drug Status
AKT1	XL418	Solid Tumors	Suspended in Phase I
AKT1	CI-1033	Cancer, NSCLC; cancer, colorectal; cancer, head and neck; cancer, thyroid; cancer, breast; cancer, mesothelioma; cancer, sarcoma, general; cancer, melanoma	Discontinued in Phase II
AKT1	Enzastaurin	Brain and Central Nervous System Tumors	Phase I
AKT1	Enzastaurin	Glioblastoma Multiforme	Phase II
AKT1	Enzastaurin	Non Hodgkin Lymphoma	Phase III
AKT1	Perifosine	Non-small Cell Lung Cancer	Terminated in Phase II
AKT1	Perifosine	Refractory Multiple Myeloma, Recurrent Malignant Glioma, Rare Sarcoma's Refractory	Phase II
AKT1	RX-0201	Metastatic Pancreatic Cancer	Phase II
AKT1	MK-2206	Colon Cancer; Rectal Cancer	Phase II
AKT1	MK2206	Colon Cancer; Rectal Cancer	Phase II
AKT1	VQD-002	Haematological malignancies; leukaemia; non-small-cell lung cancer	Phase I
AKT1	GDC-0068	Solid Tumors	Phase I

Drugs for AKT1 from TTD (Therapeutic Targets Database)