Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

AKT

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101974

Synonyms

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

Historical Background

AKT is a serine/threonine kinase member of the AGC family of protein kinases, which is conserved from primitive metazoan to humans, and it was discovered in 1977 (Staal et al. 1977). There are three isoforms of AKT in mammals (AKT1, AKT2, and AKT3), each transcribed from separate genes (Jones et al. 1991a, b; Konishi et al. 1995; Brodbeck et al. 1999). During the last decade of the twentieth century, different groups contributed to establish that all AKT isoforms contain an N-terminal pleckstrin homology (PH) domain that interacts with phosphatidylinositol (3,4,5)-trisphosphate (PIP3) (Andjelkovic et al. 1997; Franke et al. 1997), a central kinase or catalytic domain and a C-terminal domain that contains an hydrophobic motif (HM) with homology to other AGC kinases (Alessi et al. 1996). It is now known that AKT exert their action by phosphorylating a wide variety of downstream targets containing the consensus motif RXRXXS/TB where X is any amino acid and B represents a bulky hydrophobic residue (Manning and Cantley 2007; Santi and Lee 2010). It plays a central role in growth, proliferation, glucose uptake, metabolism, angiogenesis, protein translation, and cell survival, among other functions (Brazil and Hemmings 2001; Brazil et al. 2002; Fayard et al. 2005). Given the importance of the AKT pathway in all these processes, it is consistent that its deregulation has been associated with a great variety of human diseases including cardiac hypertrophy, diabetes, neuronal degeneration, vascular disorders, and cancer (Altomare and Testa 2005; Bellacosa et al. 2005; Cheung and Testa 2013). Currently, the AKT-dependent pathway is considered an attractive target for therapeutic intervention, and, consequently, a deep understanding of the molecular mechanisms underlying the regulation of this kinase activity becomes of paramount importance (Hers et al. 2011).

Regulation of AKT Activity

When bound to cognate ligands, different receptor tyrosine kinases such as the insulin-like growth factor-I receptor undergo autophosphorylation, resulting in the recruitment of adaptor molecules including insulin receptor substrate (IRS) proteins (Jones and Clemmons 1995; Dey et al. 1996). Phosphoinositide 3-kinase (PI3K) regulatory subunits complexed to p110 catalytic subunits then bind IRS and convert plasma membrane associated PIP2 to PIP3 (Geering et al. 2007). PIP3 provides a phospholipid binding substrate for signaling effector molecules such as phosphatidylinositol-dependent kinase 1 (PDK1) and AKT (Fig. 1). Once at the membrane, AKT is phosphorylated and therefore activated: PDK1 phosphorylates AKT1 at T308 within the activation loop (A-loop, T309, and T305 in AKT2 and AKT3, respectively) in the catalytic domain (Alessi et al. 1997), while S473 phosphorylation at the HM (S474 and S472 in AKT2 and AKT3, respectively) has been shown to be mediated by a number of proteins including mammalian target of rapamycin complex 2 (mTORC2) (Sarbassov et al. 2005), DNA-PK (Bozulic et al. 2008), lipid raft-associated elements (Hill et al. 2002), and autophosphorylation of AKT itself (Toker and Newton 2000). Nevertheless, phosphorylation of AKT at the HM is now considered to be mediated principally by mTORC2. Phosphorylation at AKT1 T450 (T451 and T447 in AKT2 and AKT3, respectively), also named as the turn motif (TM), in the carboxy-terminus results in increased stability of the molecule (Alessi et al. 1996).
AKT, Fig. 1

Activation of AKT is triggered when receptor tyrosine kinases bind cognate ligands such as growth factors (GF), resulting in the activation of PI3K, which in turn converts plasma membrane associated PIP2 to PIP3. After suffering initial PTMs such as ubiquitination as well as different phosphorylations, cytosolic AKT is then recruited to PM by binding to PIP3, imposing a conformational change that allows phosphorylation of AKT by PDK1 and mTORC2. Activated AKT shuttles to different subcellular compartments to phosphorylate specific substrates. Termination of AKT activation depends on dephosphorylation by PP2A and PHLPP

Recently, different groups have shown that AKT can be phosphorylated at several other residues (Fig. 2), as reviewed by Srebrow’s lab (Risso et al. 2015). AKT also undergoes other posttranslational modifications (PTMs), O-glycosylation, ubiquitination, acetylation, oxidation, and SUMOylation (Park et al. 2005; Yang et al. 2009; Sundaresan et al. 2011; Wani et al. 2011a, b; Risso et al. 2013), and very recently, it was also found that AKT can be proline-hydroxylated (Guo et al. 2016), altogether proving that regulation of AKT activity is exceptionally complex (Risso et al. 2015), as depicted in Table 1.
AKT, Fig. 2

Structure of AKT and its functional domains. The scheme shows reported phosphorylation target residues as well as the kinases responsible for these phosphorylations. Classical activation sites are shown in red (T308 and S473)

AKT, Table 1

List of reported AKT PTMs, residues and enzymes involved in these modifications, as well as consequences associated with each modification

AKT1 residue

aa

PTM

Consequences

Enzyme(s) involved

Cys

Oxidation

I

Unknown

8

Lys

K63-ubiquitination

A

TRAF6

14

Lys

K63-ubiquitination

A

TRAF6

14

Lys

Acetylation

I

SIRT1

20

Lys

Acetylation

I

SIRT1

92

Thr

Phosphorylation

S

Unknown

124

Ser

Phosphorylation

A

Unknown

125

Pro

Hydroxylation

I

EglN1, pVHL

129

Ser

Phosphorylation

A

CK2

176

Tyr

Phosphorylation

A

ACK1

276

Lys

SUMOylation

A

PIAS1; SENP1

284

Lys

K48-ubiquitination

D

MULAN

305

Thr

O-GlcNAc

I

OGT

308

Thr

Phosphorylation

A

PDK1

312

Thr

Phosphorylation

I

GSK3α

312

Thr

O-GlcNAc

I

OGT

313

Pro

Hydroxylation

I

EglN1, pVHL

315

Tyr

Phosphorylation

A

Src; PTK6

326

Tyr

Phosphorylation

A

Src; PTK7

430

Thr

O-GlcNAc

A

OGT; OGA

450

Thr

Phosphorylation

S

mTORC2

473

Ser

Phosphorylation

A

mTORC2

473

Ser

O-GlcNAc

I

OGT; OGA

474

Tyr

Phosphorylation

A

Unknown

477

Ser

Phosphorylation

A

Cdk/cyclin A

479

Thr

Phosphorylation

A

Cdk/cyclin A

479

Thr

O-GlcNAc

A

OGT; OGA

Dephosphorylation of AKT leads to the termination of AKT activation. Protein phosphatase 2A (PP2A) negatively regulates AKT activity by inducing AKT1 T308 dephosphorylation, whereas PH domain leucine-rich repeat protein phosphatase (PHLPP) suppresses AKT activity by dephosphorylating AKT1 at S473 (Millward et al. 1999; Arroyo and Hahn 2005; Gao et al. 2005; Brognard et al. 2007; Mendoza and Blenis 2007; Facchinetti et al. 2008; Blaustein et al. 2013).

AKT Targets and Subcellular Localization

Activated AKT, after recruitment to plasma membrane and phosphorylation at T308 and S473, has been shown to act on multiple targets located in the cytosol and nucleus. A number of known and putative AKT targets have been identified at different cell compartments thus far by virtue of their containing the essential AKT consensus motif RXRXXS/TB (Table 2). During the last years, it was also found that AKT can be present at nuclear membrane, mitochondria, and endoplasmic reticulum (ER) (Hosoi et al. 2007; Santi and Lee 2010). Interestingly, not only AKT but also other proteins associated to AKT survival pathway like mTOR and proteins belonging to the PI3K family have been found at the ER (Drenan et al. 2004; Matsunaga et al. 2010), and new functions of AKT have been described consistent with these localizations (Du et al. 2006; Mounir et al. 2011; Sharpe et al. 2011; Blaustein et al. 2013).
AKT, Table 2

List of reported AKT substrates showing gene and protein name, organism in which it was described, and accession ID

Gene

Protein

Organism

ACC_ID

CAP1

CENTB1

Human

Q15027

ACIN1

Acinus

Human

Q9UKV3

Acin1

Acinus

Rat

E9PST5

Acly

ACLY

Mouse

Q91V92

ADRB2

ADRB2

Human

P07550

AGAP2

CENTG1 iso2

Human

Q99490-2

AKT1

AKT1

Human

P31749

AKT1

AKT1

Mouse

P31750

AKT1S1

PRAS40

Human

Q96B36

ALYREF

THOC4

Human

Q86V81

AR

AR

Human

P10275

ARFIP2

Arfaptin 2

Human

P53365

ARHGAP22

ARHGAP22

Human

Q7Z5H3

ATXN1

Ataxin-1

Human

P54253

BABAM1

NBA1

Human

Q9NWV8

Bach2

BACH2

Mouse

P97303

BAD

BAD

Human

Q92934

Bad

BAD

Mouse

Q61337

Bad

BAD

Rat

O35147

BCL10

Bcl-10

Human

O95999

Bcl2l1

Bcl-xL

Rat

P53563

BCL2L11

BIM

Human

O43521

BECN1

Beclin 1

Human

Q14457

Bex1

BEX1

Rat

Q3MKQ2

BMI1

BMI1

Human

P35226

BRAF

BRAF

Human

P15056

BRCA1

BRCA1

Human

P38398

BTK

Btk

Human

Q06187

BTK

Btk

Human

Q06187

Cacnb2

CACNB2

Rat

Q8VGC3

CARHSP1

CARHSP1

Human

Q9Y2V2

CASP9

CASP9

Human

P55211

CBY1

CBY1

Human

Q9Y3M2

CCDC88A

Girdin

Human

Q3V6T2

CCT2

CCT2

Human

P78371

Cdc25b

CDC25B

Mouse

P30306

CDCA7

CDCA7

Human

Q9BWT1

CDK2

CDK2

Human

P24941

CDKN1A

p21Cip1

Human

P38936

Cdkn1a

p21Cip1

Mouse

P39689

CDKN1B

p27Kip1

Human

P46527

Cdkn1b

p27Kip1

Mouse

P46414

CDKN1C

p57Kip2

Human

P49918

CELF1

CELF1

Human

Q92879

CFLAR

CFLAR

Human

O15519

CHEK1

Chk1

Human

O14757

CHUK

IKKA

Human

O15111

CLK2

CLK2

Human

P49760

COPS6

COPS6

Human

Q7L5N1

Creb1

CREB

Rat

P15337

CREBBP

CBP

Human

Q92793

Crebbp

CBP

Mouse

P45481

Csnk1d

CK1D

Rat

Q06486

CSNK2A1

CK2A1

Human

P68400

CTNNB1

CTNNB1

Human

P35222

Ctnnb1

CTNNB1

Mouse

Q02248

CYTH2

Cytohesin 2

Human

Q99418

Cyth3

Cytohesin 3

Mouse

O08967

Dennd1a

DENND1A

Mouse

Q8K382

DIABLO

DIABLO

Human

Q9NR28

Dlc1

DLC1

Rat

Q63744

Dnajc5

DNAJC5

Rat

P60905

DNMT1

DNMT1

Human

P26358

DOCK6

DOCK6

Human

Q96HP0

EDC3

EDC3

Human

Q96F86

EGFR

EGFR

Human

P00533

Eif2ak3

PERK

Mouse

Q9Z2B5

Eif4b

EIF4B

Mouse

Q8BGD9

EMSY

EMSY

Human

Q7Z589

EP300

p300

Human

Q09472

EPHA2

EphA2

Human

P29317

ESR1

ER-alpha

Human

P03372

Esr2

ER-beta

Mouse

O08537

Esrrg

ERR3

Mouse

P62509

EYA1

EYA1

Human

Q99502

EZH2

EZH2

Human

Q15910

FAM129A

FAM129A

Human

Q9BZQ8

FANCA

FANCA

Human

O15360

FLNA

FLNA

Human

P21333

FLNC

FLNC

Human

Q14315

FOXA2

FOXA2

Human

Q9Y261

FOXG1

FOXG1

Human

P55316

Foxg1

FOXG1

Mouse

Q60987

FOXO1

FOXO1A

Human

Q12778

Foxo1

FOXO1A

Mouse

Q9R1E0

Foxo1

FOXO1A

Rat

G3V7R4

FOXO3

FOXO3A

Human

O43524

Foxo3

FOXO3A

Mouse

Q9WVH4

Foxo3

FOXO3A

Rat

D3ZBQ1

FOXO4

FOXO4

Human

P98177

Foxo4

FOXO4

Mouse

Q9WVH3

GAB2

GAB2

Human

Q9UQC2

Gabrb2

GABRB2

Rat

P63138

GATA1

GATA1

Human

P15976

Gata1

GATA1

Mouse

P17679

GATA2

GATA2

Human

P23769

Gja1

GJA1

Rat

P08050

Gli2

GLI2

Mouse

Q0VGT2

Golga3

GOLGA3

Mouse

P55937

Grb10

GRB10

Mouse

Q60760

Grin2c

NMDAR2C

Mouse

Q01098

Grin2c

NMDAR2C

Rat

Q00961

GSK3A

GSK3A

Human

P49840

Gsk3a

GSK3A

Rat

P18265

GSK3B

GSK3B

Human

P49841

Gsk3b

GSK3B

Mouse

Q9WV60

Gsk3b

GSK3B

Rat

P18266

H3f3b

H3 iso3

Mouse

P84244

HIST1H2BB

H2B

Human

P33778

HIST1H3A

H3

Human

P68431

HJURP

HJURP

Human

Q8NCD3

Hk2

HK2

Mouse

O08528

HMOX1

HMOX1

Human

P09601

HNRNPA1

hnRNP A1

Human

P09651

HSPB1

HSP27

Human

P04792

HTRA2

HTRA2

Human

O43464

HTT

Huntingtin

Human

P42858

ILF3

NFAT90

Human

Q12906

INVS

INVS

Human

Q9Y283

IRAK1

IRAK1

Human

P51617

IRS1

IRS1

Human

P35568

Irs1

IRS1

Rat

P35570

Irs2

IRS2

Rat

F1MAL5

ITGB3

ITGB3

Human

P05106

Itpr1

IP3R1

Rat

P29994

KAT6A

MYST3

Human

Q92794

KCNH2

Kv11.1 iso5

Human

Q12809_VAR_014388

KDM5A

JARID1A

Human

P29375

KHSRP

KHSRP

Human

Q92945

LARP6

LARP6

Human

Q9BRS8

LBR

LBR

Turkey

G1N806

LMNA

Lamin A/C

Human

P02545

Lmna

Lamin A/C

Rat

P48679

LTB4R2

LTB4R2

Human

Q9NPC1

MAP2K4

MKK4

Human

P45985

Map2k4

MKK4

Mouse

P47809

MAP3K11

MLK3

Human

Q16584

Map3k12

DLK

Mouse

Q60700

MAP3K5

ASK1

Human

Q99683

Map3k5

ASK1

Mouse

O35099

MAP3K8

Cot

Human

P41279

MAPKAP1

Sin1

Human

Q9BPZ7

MAZ

MAZ

Human

P56270

Mb21d1

MB21D1

Mouse

Q8C6L5

MDM2

MDM2

Human

Q00987

Mdm2

MDM2

Mouse

P23804

MDM4

MDM4

Human

O15151

METTL1

METTL1

Human

Q9UBP6

Mettl1

METTL1

Mouse

Q9Z120

MITF

MITF

Human

O75030

MST1R

Ron

Human

Q04912

MTOR

mTOR

Human

P42345

MXD1

Mad1

Human

Q05195

NCF1

p47phox

Human

P14598

NCOR1

N-CoR1

Human

O75376

NDRG2

NDRG2

Human

Q9UN36

Ndrg2

NDRG2

Mouse

Q9QYG0

NF2

Merlin

Human

P35240

NHE-3

NHE3

Rabbit

P26432

NHEJ1

NHEJ1

Human

Q9H9Q4

NOS3

eNOS

Human

P29474

Nos3

eNOS

Rat

Q62600

NOS3

eNOS

Pig

Q7YSG7

NOS3

eNOS

Cow

P29473

NR3C1

GR

Human

P04150

NR4A1

Nur77

Human

P22736

Nr4a1

Nur77

Rat

P22829

NUAK1

NuaK1

Human

O60285

PACS2

PACS2

Human

Q86VP3

Pak1

PAK1

Mouse

O88643

PALLD

Palladin

Human

Q8WX93

Pawr

PAR-4

Rat

Q62627

Pcbp1

hnRNP E1

Mouse

P60335

PDCD4

PDCD4

Human

Q53EL6

Pde3a

PDE3A

Mouse

Q9Z0X4

Pde3b

PDE3B

Mouse

Q61409

PDK1

PDHK1

Human

Q15118

PEA15

PEA-15

Human

Q15121

PFKFB2

PFKFB2

Human

O60825

PFKFB2

PFKFB2

Cow

P26285

PFKFB3

PFKFB3

Human

Q16875

PHB

PHB

Human

P35232

Phb

PHB

Mouse

P67778

PHF20

PHF20

Human

Q9BVI0

PIKFYVE

PIKFYVE

Human

Q9Y2I7

Pikfyve

PIKFYVE

Mouse

Q9Z1T6

PIP5K1C

PIP5K1C

Human

O60331

PKM

PKM2

Human

P14618

Pkmyt1

Myt1

Starfish

Q95YJ1

PLCG1

PLCG1

Human

P19174

Pln

PLB

Rat

P61016

Ppargc1a

PGC-1 alpha

Mouse

O70343

PPP1CA

PPP1CA

Human

P62136

PRKAA1

AMPKA1

Human

Q13131

Prkaa1

AMPKA1

Rat

P54645

Prkaa2

AMPKA2

Rat

Q09137

PRPF19

PRPF19

Human

Q9UMS4

Prph

Peripherin

Mouse

P15331

PTK2

FAK

Human

Q05397

PTPN1

PTP1B

Human

P18031

PYGO2

PYGO2

Human

Q9BRQ0

RAC1

RAC1

Human

P63000

Raf1

RAF1

Mouse

Q99N57

Raf1

RAF1

Rat

P11345

RANBP3

RANBP3

Human

Q9H6Z4

RARA

RARA

Human

P10276

RGCC

RGC32 iso2

Human

Q9H4X1-2

RICTOR

RICTOR

Human

Q6R327

RNF11

RNF11

Human

Q9Y3C5

RPS3

RPS3

Human

P23396

Rps6

S6

Mouse

P62754

Rps6

S6

Rat

P62755

RUNX2

AML3

Human

Q13950

S1PR1

EDG-1

Human

P21453

Scnn1a

ENaC-alpha

Rat

P37089

Sh2b2

APS

Rat

Q9Z200

Sh3bp4

SH3BP4

Mouse

Q921I6

SH3RF1

SH3RF1

Human

Q7Z6J0

Sik2

QIK

Mouse

Q8CFH6

SIRT6

SIRT6

Human

Q8N6T7

SKI

SKI

Human

P12755

SLC9A1

NHE1

Human

P19634

Slc9a1

NHE1

Rat

P26431

SMAD3

SMAD3

Human

P84022

Sox2

SOX2

Mouse

P48432

SP1

SP1

Human

P08047

SRPK2

SRPK2

Human

P78362

Ssb

SSB

Mouse

P32067

SSH1

SSH1

Human

Q8WYL5

STK3

MST2

Human

Q13188

STK4

MST1

Human

Q13043

SYTL1

SYTL1

Human

Q8IYJ3

TAL1

TAL1

Human

P17542

TARBP2

TRBP

Human

Q15633

TBC1D1

TBC1D1

Human

Q86TI0

Tbc1d1

TBC1D1

Mouse

Q60949

TBC1D4

AS160

Human

O60343

Tbc1d4

AS160

Mouse

Q8BYJ6

Tcf3

E2A iso2

Mouse

P15806-2

TERF1

TRF1

Human

P54274

TERT

TERT

Human

O14746

TIAM1

TIAM1

Human

Q13009

Tie1

TIE1

Mouse

Q06806

TKT

TKT

Human

P29401

TOPBP1

TOPBP1

Human

Q92547

TP53RK

PRPK

Human

Q96S44

TSC2

TSC2

Human

P49815

Tsc2

TSC2

Mouse

Q61037

Tsc2

TSC2

Rat

P49816

TTC3

TTC3

Human

P53804

TWIST1

TWIST1

Human

Q15672

UBE2S

UBE2S

Human

Q16763

Ulk1

ULK1

Mouse

O70405

USP14

USP14

Human

P54578

USP4

USP4

Human

Q13107

Usp8

USP8

Mouse

Q80U87

VCP

VCP

Human

P55072

VIM

Vimentin

Human

P08670

WEE1

Wee1

Human

P30291

WNK1

WNK1

Human

Q9H4A3

XIAP

XIAP

Human

P98170

YAP1

YAP1

Human

P46937

YBX1

YB-1

Human

P67809

YWHAZ

14-3-3 zeta

Human

P63104

ZFP36L1

BRF1

Human

Q07352

ZYX

Zyxin

Human

Q15942

AKT in Cancer

Deregulation of the AKT pathway is associated with a variety of human cancers and several mouse models with activated AKT support its role in cancer development (Altomare and Testa 2005; Fayard et al. 2005; Toker and Yoeli-Lerner 2006). Gene amplification or overexpression of each isoform has been linked to a variety of different cancers. For instance, overexpression of insulin-like growth factor-binding protein-5 helps to accelerate progression to androgen independence in the prostate tumor model through activation of the PI3K/AKT pathway (Miyake et al. 2000). Aberrant AKT activation is observed in various human cancers, and importantly, AKT1, AKT2, and AKT3 isoforms are found to be overexpressed in human cancers (Staal 1987; Cheng et al. 1992, 1996; Bellacosa et al. 1995; Nakatani et al. 1999; Stahl et al. 2004). Recent studies show that AKT1 mutations were observed in a subset of human cancers and associated with AKT hyperactivation (Carpten et al. 2007; Kim et al. 2008; Malanga et al. 2008; Mohamedali et al. 2008; Shoji et al. 2009; Zilberman et al. 2009; Askham et al. 2010). The role of AKT in cancer development has been supported by numerous animal tumor models. For example, Pten+/− mice with aberrant AKT activation develop multiple tumors, which can be inhibited by AKT1 deficiency (Di Cristofano et al. 2001; Chen et al. 2006). AKT was also shown to regulate hormone independence and tumor differentiation in breast cancer (Riggio et al. 2012). In addition, the prostate-specific expression of constitutively active AKT1 in mice leads to prostate intraepithelial neoplasia (PIN) (Majumder et al. 2003, 2004). These results highlight the critical role of the PI3K/AKT pathway in cancer development.

AKT as a Target for Therapeutic Intervention

Taking the critical role of AKT in tumorigenesis into account, it is not surprising that this pathway is considered as an attractive target for therapeutic treatment of cancer, and actually several specific inhibitors of AKT have been found, some of which are being tested in clinical trials. The benzimidazole derivative AKT inhibitor-IV, for instance, exhibits potent anticancer and antiviral activity (Kau et al. 2003). Some analogs with enhanced antiviral activity and cytotoxicity but lower toxicity have been developed (Sun et al. 2011). Another small molecule, BI-69A11 was shown to elicit effective regression of xenograft melanoma tumors (Gaitonde et al. 2009), while the drug TCN-P binds to the PH domain of AKT, blocking its recruitment to the membrane and triggering antiproliferative and proapoptotic activities (Berndt et al. 2010). The first allosteric AKT inhibitor to enter clinical development was MK-2206, a molecule which is well tolerated and has demonstrated anticancer properties in preclinical and early-phase clinical studies (Biondo et al. 2011; Kalinsky et al. 2011). Another PI3K/AKT inhibitor, buparlisib, combined with the MAPK inhibitor MEK162, is capable of reducing tumor growth in vitro and in vivo, exhibiting strong antitumor activity (Talbert et al. 2016). Other PI3-kinase-AKT-mTOR pathway inhibitors have been also described and reviewed (Lauring et al. 2013).

Summary

AKT is a serine/threonine kinase member of the AGC family of protein kinases. The three isoforms of AKT (AKT1/2/3) play a central role in growth, proliferation, glucose uptake, metabolism, protein translation, and cell survival. Given the importance of the AKT pathway in all these processes, it is not surprising that its deregulation is associated with a variety of human diseases including cardiac hypertrophy, diabetes, neuronal degeneration, vascular disorders, and cancer. Therefore, AKT-dependent pathways are considered an attractive target for therapeutic intervention. AKT contains an N-terminal pleckstrin homology domain which interacts with PIP2 and PIP3, a central kinase domain, and a C-terminal domain that contains a hydrophobic motif with homology to other AGC kinases. When bound to cognate ligands, receptor tyrosine kinases such as the insulin-like growth factor-I receptor undergo autophosphorylation, resulting in the recruitment of adaptor molecules. PI3K regulatory subunits complexed to p110 catalytic subunits in turn convert plasma membrane associated PIP2 to PIP3. PIP3 recruits AKT to the plasma membrane where AKT gets phosphorylated and therefore activated. Dephosphorylation of AKT leads to the termination of AKT activation. Activated AKT acts on multiple targets located in the cytoplasm and nucleus. A number of known and putative AKT targets have been identified thus far by virtue of their containing the essential AKT consensus motif (RXRXXS/TB) where X is any amino acid and B represents a bulky hydrophobic residue. Deregulation of the AKT pathway is associated with a variety of human diseases including cardiac hypertrophy, diabetes, neuronal degeneration, vascular disorders, and cancer, and therefore this pathway is considered an attractive target for therapeutic intervention.

See Also

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos AiresBuenos AiresArgentina
  2. 2.CONICET-Universidad de Buenos AiresInstituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE)Buenos AiresArgentina