PI3K-AKT Signaling

PATHWAYS & KEY MOLECULAR TARGETS

PI3K-AKT Signaling Mechanism of Activation and Major Phosphorylation Sites of AKT1 Agonists

Cytokine Cytokine Receptor

Integrin

Growth Factor

GPCR

FAK

PI3K

PI3K

IRS-1

JAK1

ILK

Gab1 Gab2

α/β

PI3K

TO

SYK

Glut4

DEPTOR PRR5

Rictor

Sin1

PDK1

GBL GβL

Membrane Recruitment & Activation

PDK1

Glucose Import

PHLPP eNOS

PDK1 ACLY

Synthesis of Fatty Acids

GYS1

Glycogen Synthesis

S6

Translational Initiation

RPS6

mT OR

C1

PI3K

Raptor AKT

mTOR TSC2

DEPTOR

4EBP1

RAC, BTK, PDK1-SGK3 mTORC2-NFkB, mTORC2-cMyc

Glycolysis

PFKFB2

G βL

PDCD4

TSC1

PRAS40 MEK 1/2

DNA-PK FOXO1

Apoptosis

BCL2

Cell Survival

BIM Glycogen Synthase

Bax

Gene Transcription

AR

Wnt-β-catenin signaling

Caspase 9

BAD

Girdin

p21

GSK3B

14-3-3

Migration CREB

MDM2

Survival Genes

Cyclin D1

PP1

Wee

p27

MYT1

IKKa

IKB NFKB

IKB Degradation Cell Proliferation

NFAT

p53 Degradation

Cell Proliferation

CREB FKH2 p53

MDM2

NFKB

NFAT GATA4

Pathway Key Direct Activation

s cleu

Nu

m

las

op Cyt

Direct Inhibition

PI3K Independent AKT Activity Ack I, IKK epsilon, TBK1, Scr kinase, PTK6

Tumor Growth

X

AKT

AKT

Tumor Growth

X

PI3K

Small Molecule Inhibitors of AKT*

Cell proliferation

Survival signaling

Target Protein (s)

Inhibitor (s)

Cyclin D1 p21/Cip p27/Kip Myt1 Wee1

Bad MDM2/p53 FOXO1 Bcl-2 Bax

Akt (PKB)

Akti-1/2, API-1, API-2, 10-DEBC hydrochloride, FPA 124, GSK 690693, Perifosine, SC 66

Akt and PDK1

PHT 427

mTOR

Rapamycin, Torin 1, AZD 3147, eCF 309

Metabolism

Translational Control

GSK-3 PFKFB2 PIP5K AS160 TBC1D4 PDE3B Neuronal Function

S6 kinase RPS6 TSC1 mTOR PDCD4

PDK1

GSK 2334470, BX 795, OSU 03012

PIP3

PIT 1

PI3K

LY 294002, Wortmannin, PI 828

PI3K p110α

A66

PI3Kβ

AZD 6482

PI3K p110δ

PI 3065

Huntingtin Ataxin-1 GABAA receptor NFkB

TSC-mTORC1 FOXO1 GSK3β ACLY

PI3K γ

AS 605240

Immunity

Invasion/Migration

Others

Palladin Girdin Rac/GTP

WNK1 eNOS LMNA

Other molecules for AKT Signaling*

Multistep Activation Multistep Inhibition

Plasma Membrane

Ser473

Thr308

Thr308

PI3K-AKT Signaling: Processes & Targets*

Ras

Autophagy

XIAP

P

Organization of Nuclear Protein

LMNA

RAF1

ATG13

Regulatory domain

P

AKT Independent PI3K Activity

Cardiovascular Homeostasis

Huntingtin

P70S6K

AKT

Kinase domain

Linker

Glucose Transport

PIP5K AS160

14-3-3

PH domain

P

PIP3

PP2A

Neuroprotection

p110

LYN

P

PIP3 PIP3

PIP2

AKT1

Ser473

DNA-PK

SGK3

C2

mTOR

Membrane Recruitment & Activation

p85

PI3K

BCAP

PIP2

m

α/β

g

PI3K

R

PTEN

ATAXIN

PTEN

BCR

ml

PTEN

PIP3

AKT

GBP Gα-GTP PI3K

Paxillin

PIP2

Aggregation & Neurodegeneration

Growth Factors

mlg Gβγ

Synaptic Signaling

CD19 Ag

RTK GABAAR

mTORC2

Translocation Independant Activation

Small molecule

Description

SC 79

Activator of Akt

740 YP

Cell permeable activator of PI3K

Akt/SKG Substrate Peptide

Synthetic substrate of Akt/PKB

AKTide-2T

Peptide substrate for Akt/PKB

PI3K-AKT Signaling in Diseases Overgrowth syndromes, cancer (growth, angiogenesis and metastasis), cardiovascular diseases, glucose metabolism related disorders (insulin resistance and diabetes), autoimmune diseases and inflammation, and neurodegeneration related disorders. *Visit www.novusbio.com, www.rndsystems.com and www.tocris.com to learn more.

www.novusbio.com

PS-PM_AKT_23311