Target General Infomation
Target ID
T20891
Former ID
TTDR00273
Target Name
3-phosphoinositide dependent protein kinase-1
Gene Name
PDPK1
Synonyms
3'-phosphoinositide dependent kinase 1; 3-Phosphoinositide-dependent kinase-1; HPDK1; PDPK1
Target Type
Clinical Trial
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
Function
Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF- kappa-B activation in macrophages. Isoform 3 is catalytically inactive.
BioChemical Class
Kinase
UniProt ID
EC Number
EC 2.7.11.1
Sequence
MARTTSQLYDAVPIQSSVVLCSCPSPSMVRTQTESSTPPGIPGGSRQGPAMDGTAAEPRP
GAGSLQHAQPPPQPRKKRPEDFKFGKILGEGSFSTVVLARELATSREYAIKILEKRHIIK
ENKVPYVTRERDVMSRLDHPFFVKLYFTFQDDEKLYFGLSYAKNGELLKYIRKIGSFDET
CTRFYTAEIVSALEYLHGKGIIHRDLKPENILLNEDMHIQITDFGTAKVLSPESKQARAN
SFVGTAQYVSPELLTEKSACKSSDLWALGCIIYQLVAGLPPFRAGNEYLIFQKIIKLEYD
FPEKFFPKARDLVEKLLVLDATKRLGCEEMEGYGPLKAHPFFESVTWENLHQQTPPKLTA
YLPAMSEDDEDCYGNYDNLLSQFGCMQVSSSSSSHSLSASDTGLPQRSGSNIEQYIHDLD
SNSFELDLQFSEDEKRLLLEKQAGGNPWHQFVENNLILKMGPVDKRKGLFARRRQLLLTE
GPHLYYVDPVNKVLKGEIPWSQELRPEAKNFKTFFVHTPNRTYYLMDPSGNAHKWCRKIQ
EVWRQRYQSHPDAAVQ
Drugs and Mode of Action
Drug(s) AR-12 Drug Info Phase 1 Lymphoma [522785], [542919]
Modulator AR-12 Drug Info [1572591]
Inhibitor BX-795 Drug Info [527484]
BX-912 Drug Info [527484]
compound 1 Drug Info [530572]
GSK-2334470 Drug Info [525397]
PF-5177624 Drug Info [552009]
Phosphonoserine Drug Info [551393]
PHT-427 Drug Info [530764]
Pathways
KEGG Pathway PPAR signaling pathway
FoxO signaling pathway
Sphingolipid signaling pathway
mTOR signaling pathway
PI3K-Akt signaling pathway
AMPK signaling pathway
Focal adhesion
T cell receptor signaling pathway
Fc epsilon RI signaling pathway
Neurotrophin signaling pathway
Insulin signaling pathway
Thyroid hormone signaling pathway
Aldosterone-regulated sodium reabsorption
Toxoplasmosis
Hepatitis C
Proteoglycans in cancer
Endometrial cancer
Prostate cancer
Non-small cell lung cancer
Choline metabolism in cancer
PANTHER Pathway Inflammation mediated by chemokine and cytokine signaling pathway
Insulin/IGF pathway-protein kinase B signaling cascade
Interleukin signaling pathway
PDGF signaling pathway
PI3 kinase pathway
p53 pathway
Ras Pathway
p53 pathway feedback loops 2
CCKR signaling map ST
Pathway Interaction Database BCR signaling pathway
Insulin Pathway
TCR signaling in na&amp
#xef
ve CD4+ T cells
Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
TCR signaling in na&amp
ve CD8+ T cells
FAS (CD95) signaling pathway
mTOR signaling pathway
CXCR4-mediated signaling events
IGF1 pathway
Class I PI3K signaling events
ErbB1 downstream signaling
IL8- and CXCR2-mediated signaling events
CXCR3-mediated signaling events
VEGFR1 specific signals
Signaling events mediated by Stem cell factor receptor (c-Kit)
Signaling events mediated by VEGFR1 and VEGFR2
Class I PI3K signaling events mediated by Akt
IL8- and CXCR1-mediated signaling events
Trk receptor signaling mediated by PI3K and PLC-gamma
FGF signaling pathway
TGF-beta receptor signaling
PathWhiz Pathway Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
Insulin Signalling
Reactome GPVI-mediated activation cascade
PIP3 activates AKT signaling
Activation of AKT2
Role of LAT2/NTAL/LAB on calcium mobilization
FCERI mediated NF-kB activation
Integrin alphaIIb beta3 signaling
CD28 dependent PI3K/Akt signaling
CTLA4 inhibitory signaling
gamma signalling through PI3Kgamma
VEGFR2 mediated vascular permeability
VEGFR2 mediated cell proliferation
CLEC7A (Dectin-1) signaling
RHO GTPases activate PKNs
Constitutive Signaling by AKT1 E17K in Cancer
WikiPathways Serotonin HTR1 Group and FOS Pathway
TCR Signaling Pathway
Insulin Signaling
EGF/EGFR Signaling Pathway
Focal Adhesion
Cardiac Hypertrophic Response
Fc epsilon receptor (FCERI) signaling
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
PIP3 activates AKT signaling
BDNF signaling pathway
Interleukin-11 Signaling Pathway
B Cell Receptor Signaling Pathway
Signaling Pathways in Glioblastoma
TSH signaling pathway
TCR signaling
Signaling by Insulin receptor
Integrin-mediated Cell Adhesion
GPVI-mediated activation cascade
GPCR downstream signaling
Costimulation by the CD28 family
MicroRNAs in cardiomyocyte hypertrophy
References
Ref 522785ClinicalTrials.gov (NCT00978523) Study of AR-12 (2-Amino-N-[4-[5-(2 Phenanthrenyl)-3-(Trifluoromethyl)-1H-pyrazol-1-yl] Phenyl]-Acetamide) in Adult Patients With Advanced or Recurrent Solid Tumors orLymphoma. U.S. National Institutes of Health.
Ref 542919(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8005).
Ref
Ref 525397Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. Oncogene. 2014 Aug 21;33(34):4330-9.
Ref 527484Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74. Epub 2005 Mar 16.
Ref 5305722,3,5-Trisubstituted pyridines as selective AKT inhibitors. Part II: Improved drug-like properties and kinase selectivity from azaindazoles. Bioorg Med Chem Lett. 2010 Jan 15;20(2):679-83.
Ref 530764Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Mol Cancer Ther. 2010 Mar;9(3):706-17.
Ref 551393How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
Ref 552009Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. PLoS One. 2012;7(10):e48402.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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