InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: AKT2

Summary

InnateDB Protein

IDBP-246473.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

AKT2

Protein Name

v-akt murine thymoma viral oncogene homolog 2

Synonyms

HIHGHH; PKBB; PKBBETA; PRKBB; RAC-BETA;

Species

Homo sapiens

Ensembl Protein

ENSP00000375892

InnateDB Gene

IDBG-51270 (AKT2)

Protein Structure

UniProt Annotation

Function

AKT2 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. This 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. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)- response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development.One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'.

Subcellular Localization

Cytoplasm. Nucleus. Cell membrane; Peripheral membrane protein. Note=Localizes within both nucleus and cytoplasm of proliferative primary myoblasts and mostly within the nucleus of differentiated primary myoblasts. By virtue of the N-terminal PH domain, is recruited to sites of the plasma membrane containing increased PI(3,4,5)P3 or PI(3,4)P2, cell membrane targeting is also facilitared by interaction with CLIP3.

Disease Associations

Note=Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma.Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269PubMed:15166380, ECO:0000269PubMed:19164855}. Note=The disease is caused by mutations affecting the gene represented in this entry.Hypoinsulinemic hypoglycemia with hemihypertrophy (HIHGHH) [MIM:240900]: A disorder characterized by hypoglycemia, low insulin levels, low serum levels of ketone bodies and branched-chain amino acids, left-sided hemihypertrophy, neonatal macrosomia, reduced consciousness and hypoglycemic seizures. {ECO:0000269PubMed:21979934}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Expressed in all cell types so far analyzed.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 75 experimentally validated interaction(s) in this database.
They are also associated with 9 interaction(s) predicted by orthology.

Experimentally validated
Total	75 [view]
Protein-Protein	74 [view]
Protein-DNA	1 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	9 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016301	kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups

Biological Process

GO:0001934	positive regulation of protein phosphorylation
GO:0005978	glycogen biosynthetic process
GO:0006006	glucose metabolic process
GO:0006417	regulation of translation
GO:0006464	cellular protein modification process
GO:0006468	protein phosphorylation
GO:0006915	apoptotic process
GO:0007165	signal transduction
GO:0008286	insulin receptor signaling pathway
GO:0008643	carbohydrate transport
GO:0010748	negative regulation of plasma membrane long-chain fatty acid transport
GO:0010907	positive regulation of glucose metabolic process
GO:0030334	regulation of cell migration
GO:0031340	positive regulation of vesicle fusion
GO:0032000	positive regulation of fatty acid beta-oxidation
GO:0032287	peripheral nervous system myelin maintenance
GO:0032859	activation of Ral GTPase activity
GO:0032869	cellular response to insulin stimulus
GO:0045444	fat cell differentiation
GO:0045725	positive regulation of glycogen biosynthetic process
GO:0046326	positive regulation of glucose import
GO:0060644	mammary gland epithelial cell differentiation
GO:0061024	membrane organization
GO:0065002	intracellular protein transmembrane transport
GO:0071156	regulation of cell cycle arrest
GO:0072659	protein localization to plasma membrane
GO:0090314	positive regulation of protein targeting to membrane
GO:2000147	positive regulation of cell motility
GO:2001275	positive regulation of glucose import in response to insulin stimulus

Cellular Component

GO:0005634	nucleus
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0005938	cell cortex
GO:0032587	ruffle membrane

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR000961 AGC-kinase, C-terminal
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR001849 Pleckstrin homology domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR017892 Protein kinase, C-terminal
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714
PF00169
PF00433

PRINTS

PR00109

PIRSF

SMART

SM00133
SM00233
SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt