InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: AKT1

Summary

InnateDB Protein

IDBP-587349.3

Last Modified

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

Gene Symbol

AKT1

Protein Name

v-akt murine thymoma viral oncogene homolog 1

Synonyms

AKT; CWS6; PKB; PKB-ALPHA; PRKBA; RAC; RAC-ALPHA;

Species

Homo sapiens

Ensembl Protein

ENSP00000450688

InnateDB Gene

IDBG-22709 (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. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro- apoptotic activity. Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53.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.

Subcellular Localization

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.

Disease Associations

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. {ECO:0000269PubMed:17611497}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. Note=The gene represented in this entry may be involved in disease pathogenesis.Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.Proteus syndrome (PROTEUSS) [MIM:176920]: A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes. {ECO:0000269PubMed:21793738}. Note=The disease is caused by mutations affecting the gene represented in this entry.Cowden syndrome 6 (CWS6) [MIM:615109]: A form of Cowden syndrome, a hamartomatous polyposis syndrome with age-related penetrance. Cowden syndrome is characterized by hamartomatous lesions affecting derivatives of ectodermal, mesodermal and endodermal layers, macrocephaly, facial trichilemmomas (benign tumors of the hair follicle infundibulum), acral keratoses, papillomatous papules, and elevated risk for development of several types of malignancy, particularly breast carcinoma in women and thyroid carcinoma in both men and women. Colon cancer and renal cell carcinoma have also been reported. Hamartomas can be found in virtually every organ, but most commonly in the skin, gastrointestinal tract, breast and thyroid. Note=The disease is caused by mutations affecting the gene represented in this entry.

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. {ECO:0000269PubMed:1718748, ECO:0000269PubMed:17932490, ECO:0000269PubMed:20333297}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 482 experimentally validated interaction(s) in this database.
They are also associated with 26 interaction(s) predicted by orthology.

Experimentally validated
Total	482 [view]
Protein-Protein	477 [view]
Protein-DNA	4 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	26 [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: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: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:0001934	positive regulation of protein phosphorylation
GO:0001938	positive regulation of endothelial cell proliferation
GO:0005979	regulation of glycogen biosynthetic process
GO:0006417	regulation of translation
GO:0006464	cellular protein modification process
GO:0006468	protein phosphorylation
GO:0006469	negative regulation of protein kinase activity
GO:0006809	nitric oxide biosynthetic process
GO:0006915	apoptotic process
GO:0006924	activation-induced cell death of T cells
GO:0007165	signal transduction
GO:0007173	epidermal growth factor receptor signaling pathway
GO:0007186	G-protein coupled receptor signaling pathway
GO:0007596	blood coagulation
GO:0008283	cell proliferation
GO:0008286	insulin receptor signaling pathway
GO:0008543	fibroblast growth factor receptor signaling pathway
GO:0009408	response to heat
GO:0010467	gene expression
GO:0010507	negative regulation of autophagy
GO:0010748	negative regulation of plasma membrane long-chain fatty acid transport
GO:0010907	positive regulation of glucose metabolic process
GO:0010951	negative regulation of endopeptidase activity
GO:0010975	regulation of neuron projection development
GO:0016070	RNA metabolic process
GO:0016071	mRNA metabolic process
GO:0016310	phosphorylation
GO:0018105	peptidyl-serine phosphorylation
GO:0030154	cell differentiation
GO:0030168	platelet activation
GO:0030307	positive regulation of cell growth
GO:0030334	regulation of cell migration
GO:0031018	endocrine pancreas development
GO:0031295	T cell costimulation
GO:0031659	positive regulation of cyclin-dependent protein kinase activity involved in G1/S
GO:0031999	negative regulation of fatty acid beta-oxidation
GO:0032270	positive regulation of cellular protein metabolic process
GO:0032869	cellular response to insulin stimulus
GO:0033138	positive regulation of peptidyl-serine phosphorylation
GO:0034405	response to fluid shear stress
GO:0035556	intracellular signal transduction
GO:0038095	Fc-epsilon receptor signaling pathway
GO:0043066	negative regulation of apoptotic process
GO:0043154	negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0043536	positive regulation of blood vessel endothelial cell migration
GO:0044281	small molecule metabolic process
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:0045861	negative regulation of proteolysis
GO:0046209	nitric oxide metabolic process
GO:0046326	positive regulation of glucose import
GO:0046777	protein autophosphorylation
GO:0046889	positive regulation of lipid biosynthetic process
GO:0048009	insulin-like growth factor receptor signaling pathway
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0048015	phosphatidylinositol-mediated signaling
GO:0050999	regulation of nitric-oxide synthase activity
GO:0051000	positive regulation of nitric-oxide synthase activity
GO:0051091	positive regulation of sequence-specific DNA binding transcription factor activity
GO:0060644	mammary gland epithelial cell differentiation
GO:0061024	membrane organization
GO:0070141	response to UV-A
GO:0090004	positive regulation of establishment of protein localization to plasma membrane
GO:0090201	negative regulation of release of cytochrome c from mitochondria
GO:0097193	intrinsic apoptotic signaling pathway
GO:1900740	positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway
GO:1901976	regulation of cell cycle checkpoint
GO:1902176	negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway
GO:2001240	negative regulation of extrinsic apoptotic signaling pathway in absence of ligand

Cellular Component

GO:0005634	nucleus
GO:0005654	nucleoplasm
GO:0005737	cytoplasm
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0015630	microtubule cytoskeleton

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