InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Akt1

Summary

InnateDB Protein

IDBP-174625.6

Last Modified

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

Gene Symbol

Akt1

Protein Name

thymoma viral proto-oncogene 1

Synonyms

Akt; PKB; PKB/Akt; PKBalpha; Rac;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000001780

InnateDB Gene

IDBG-174623 (Akt1)

Protein Structure

UniProt Annotation

Function

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. 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. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr- 117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (By similarity). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (By similarity). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (By similarity). {ECO:0000250}.AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation. {ECO:0000269PubMed:10454575, ECO:0000269PubMed:11282895, ECO:0000269PubMed:11579209, ECO:0000269PubMed:11994271, ECO:0000269PubMed:12783884, ECO:0000269PubMed:18288188, ECO:0000269PubMed:19778506, ECO:0000269PubMed:20333297, ECO:0000269PubMed:22057101, ECO:0000269PubMed:9415393}.

Subcellular Localization

Cytoplasm. Nucleus. Cell membrane {ECO:0000250}. Note=Nucleus after activation by integrin-linked protein kinase 1 (ILK1) (By similarity). 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. {ECO:0000250}.

Disease Associations

Tissue Specificity

Widely expressed. Low levels found in liver with slightly higher levels present in thymus and testis. {ECO:0000269PubMed:8437858}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 86 experimentally validated interaction(s) in this database.
They are also associated with 254 interaction(s) predicted by orthology.

Experimentally validated
Total	86 [view]
Protein-Protein	86 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	254 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004712	protein serine/threonine/tyrosine kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0005080	protein kinase C binding
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0005547	phosphatidylinositol-3,4,5-trisphosphate binding
GO:0016301	kinase activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0019899	enzyme binding
GO:0019901	protein kinase binding
GO:0030235	nitric-oxide synthase regulator activity
GO:0042802	identical protein binding
GO:0043325	phosphatidylinositol-3,4-bisphosphate binding
GO:0071889	14-3-3 protein binding

Biological Process

GO:0000060	protein import into nucleus, translocation
GO:0001649	osteoblast differentiation
GO:0001893	maternal placenta development
GO:0001934	positive regulation of protein phosphorylation
GO:0001938	positive regulation of endothelial cell proliferation
GO:0005977	glycogen metabolic process
GO:0005978	glycogen biosynthetic process
GO:0005979	regulation of glycogen biosynthetic process
GO:0006006	glucose metabolic process
GO:0006412	translation
GO:0006417	regulation of translation
GO:0006468	protein phosphorylation
GO:0006469	negative regulation of protein kinase activity
GO:0006924	activation-induced cell death of T cells
GO:0006954	inflammatory response
GO:0007010	cytoskeleton organization
GO:0007165	signal transduction
GO:0007281	germ cell development
GO:0007568	aging
GO:0008286	insulin receptor signaling pathway
GO:0008637	apoptotic mitochondrial changes
GO:0009725	response to hormone
GO:0010507	negative regulation of autophagy
GO:0010748	negative regulation of plasma membrane long-chain fatty acid transport
GO:0010765	positive regulation of sodium ion transport
GO:0010907	positive regulation of glucose metabolic process
GO:0010951	negative regulation of endopeptidase activity
GO:0010975	regulation of neuron projection development
GO:0015758	glucose transport
GO:0016310	phosphorylation
GO:0016567	protein ubiquitination
GO:0018105	peptidyl-serine phosphorylation
GO:0030030	cell projection organization
GO:0030163	protein catabolic process
GO:0030212	hyaluronan metabolic process
GO:0030307	positive regulation of cell growth
GO:0030334	regulation of cell migration
GO:0031018	endocrine pancreas development
GO:0031659	positive regulation of cyclin-dependent protein kinase activity involved in G1/S
GO:0031999	negative regulation of fatty acid beta-oxidation
GO:0032094	response to food
GO:0032270	positive regulation of cellular protein metabolic process
GO:0032287	peripheral nervous system myelin maintenance
GO:0032436	positive regulation of proteasomal ubiquitin-dependent protein catabolic process
GO:0032869	cellular response to insulin stimulus
GO:0032880	regulation of protein localization
GO:0033138	positive regulation of peptidyl-serine phosphorylation
GO:0034405	response to fluid shear stress
GO:0035556	intracellular signal transduction
GO:0042593	glucose homeostasis
GO:0042640	anagen
GO:0043065	positive regulation of apoptotic process
GO:0043066	negative regulation of apoptotic process
GO:0043154	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0043491	protein kinase B signaling
GO:0043536	positive regulation of blood vessel endothelial cell migration
GO:0045087	innate immune response (InnateDB)
GO:0045429	positive regulation of nitric oxide biosynthetic process
GO:0045600	positive regulation of fat cell differentiation
GO:0045725	positive regulation of glycogen biosynthetic process
GO:0045792	negative regulation of cell size
GO:0045861	negative regulation of proteolysis
GO:0045907	positive regulation of vasoconstriction
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046326	positive regulation of glucose import
GO:0046329	negative regulation of JNK cascade
GO:0046889	positive regulation of lipid biosynthetic process
GO:0048009	insulin-like growth factor receptor signaling pathway
GO:0051000	positive regulation of nitric-oxide synthase activity
GO:0051091	positive regulation of sequence-specific DNA binding transcription factor activity
GO:0051146	striated muscle cell differentiation
GO:0060709	glycogen cell differentiation involved in embryonic placenta development
GO:0060716	labyrinthine layer blood vessel development
GO:0070141	response to UV-A
GO:0071260	cellular response to mechanical stimulus
GO:0071363	cellular response to growth factor stimulus
GO:0071364	cellular response to epidermal growth factor stimulus
GO:0071407	cellular response to organic cyclic compound
GO:0071456	cellular response to hypoxia
GO:0090004	positive regulation of establishment of protein localization to plasma membrane
GO:0090201	negative regulation of release of cytochrome c from mitochondria
GO:0097011	cellular response to granulocyte macrophage colony-stimulating factor stimulus
GO:0097194	execution phase of apoptosis
GO:1901653	cellular response to peptide

Cellular Component

GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005737	cytoplasm
GO:0005739	mitochondrion
GO:0005819	spindle
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0005911	cell-cell junction
GO:0015630	microtubule cytoskeleton
GO:0036064	ciliary basal body

Protein Structure and Domains

PDB ID

MGI:87986

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