Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

PDPK1 (O15530) - Overview - Molecular Target Synopsis

Protein


PDPK1, 3-phosphoinositide-dependent protein kinase 1
Enzyme Classification 2.7.11.1
UniProt O15530

Also Known as PDPK1_HUMAN, PDPK1, PDK1

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. Homodimer in its autoinhibited state. Active as monomer. Interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form interacts with SRC, RASA1 and CRK (via their SH2 domains). Interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form interacts with PTPN6. The Ser-241 phosphorylated form interacts with YWHAH and YWHAQ. Binds INSR in response to insulin. Interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. Interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.

5MRD
HUMAN PDK1-PKCIOTA KINASE CHIMERA IN COMPLEX WITH ALLOSTERIC COMPOUND PS267 BOUND TO THE PIF-POCKET
RCSB/PDB
Inspect Structure
See all 3D Structures for PDPK1

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: PDPK1 is active in the following subcellular-locations: cell junction, cell membrane, cytoplasm, focal adhesion, nucleus.
GO terms: PDPK1 is active in the following subcellular-locations: cell projection, cytoplasm, cytoplasmic vesicle, cytosol, focal adhesion, nucleoplasm, perikaryon, plasma membrane, postsynaptic density.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project PDPK1 has gain in 1 cell-lines, loss in 0 cell-lines and no signal in 1004 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MCF7, MALME_3M, T47D

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: NCI-H187, HM7, MDA-MB-361

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, HSMM, NHLF

(see details)

RNA Interference


PDPK1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: HCC38, TE11. (see details)

3D Structures


For PDPK1 there are:
68 structures (86 chains) solved
66 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

PDPK1 is solved in complex with the approved drug(s):

ADN/ADENOSINE (5LVN_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


PDPK1 has been screened with 1944 compounds (2749 bioactivities), 589 compounds have bioactivities that show binding affinity of <= 500nM (738 bioactivities). (see details)