PDPK1: 3-Phosphoinositide-Dependent Protein Kinase 1
A master kinase in PI3K/AKT signaling, central to cell growth, survival, and metabolism.
Gene Information Card
| Symbol | PDPK1 |
|---|---|
| Full Name | 3-phosphoinositide dependent protein kinase 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 16p13.3 |
| NCBI Gene ID | 5170 ncbi.nlm.nih.gov/gene/5170 |
| Ensembl ID | ENSG00000140992 |
| UniProt ID | O15530 |
| OMIM ID | 605213 |
| HGNC ID | 8816 |
| Aliases | PDK1, PDPK2P, PRO0461 |
Description
PDPK1 encodes 3-phosphoinositide-dependent protein kinase 1 (PDK1), a master kinase that phosphorylates and activates members of the AGC kinase family, including AKT, PKC, S6K, and SGK. PDK1 is a key mediator of PI3K signaling, regulating cell growth, proliferation, survival, and metabolism. Its activity is controlled by membrane localization and phosphorylation at Ser241. Dysregulation of PDPK1 is implicated in various cancers and metabolic disorders.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | Overexpression or gain-of-function mutations lead to constitutive activation of AKT and downstream survival pathways, promoting tumorigenesis. | COSMIC; PMID: 22926525 |
| Breast cancer | Amplification and overexpression of PDPK1 correlate with poor prognosis and resistance to therapy. | ClinVar; PMID: 20516152 |
| Non-small cell lung cancer | Activating mutations and increased PDK1 activity drive AKT signaling and cell proliferation. | COSMIC; PMID: 24013665 |
| Glioblastoma | PDK1 overexpression enhances PI3K/AKT signaling, contributing to tumor growth and invasion. | PMID: 21502544 |
| Prostate cancer | Elevated PDPK1 expression associated with aggressive disease and metastasis. | PMID: 21947067 |
| Type 2 diabetes | Impaired PDK1 signaling in insulin-responsive tissues contributes to insulin resistance. | OMIM: 605213; PMID: 16601693 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 12.5 | Medium |
| Heart | 8.3 | Medium |
| Liver | 6.1 | Low |
| Kidney | 7.9 | Medium |
| Lung | 9.2 | Medium |
| Pancreas | 5.4 | Low |
| Skeletal muscle | 10.1 | Medium |
| Testis | 14.8 | High |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 11.3 | Cervical cancer cell line |
| A549 | 9.8 | Lung cancer cell line |
| MCF7 | 10.5 | Breast cancer cell line |
| HEK293 | 8.7 | Embryonic kidney cell line |
| K562 | 7.2 | Leukemia cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.721C>T (p.Arg241Trp) | Missense | 0.2% (COSMIC) | Potential gain-of-function; alters kinase domain |
| c.1100A>G (p.Tyr367Cys) | Missense | 0.1% (COSMIC) | Unknown significance |
| c.1438G>A (p.Gly480Arg) | Missense | 0.05% (COSMIC) | Likely loss-of-function |
| Amplification | Copy number gain | ~3% (TCGA) | Overexpression; associated with poor prognosis |
Mutation functional classification
Loss of Function (LOF)
Rare missense mutations in the kinase domain (e.g., p.Gly480Arg) reduce catalytic activity and downstream signaling.
Gain of Function (GOF)
Amplification and certain missense mutations (e.g., p.Arg241Trp) enhance PDK1 activity, leading to constitutive AKT activation.
Dominant Negative (DN)
Not well documented; some kinase-dead mutants may exert dominant-negative effects by competing for substrates.
View complete mutation data：
Gene Ontology (GO)
Pathways
• PI3K-Akt signaling pathway (KEGG: hsa04151)
• mTOR signaling pathway (KEGG: hsa04150)
• Insulin signaling pathway (KEGG: hsa04910)
• Fc epsilon RI signaling pathway (KEGG: hsa04664)
• T cell receptor signaling pathway (KEGG: hsa04660)
Protein Summary
PDK1 is a 556-amino acid serine/threonine kinase with an N-terminal kinase domain and a C-terminal pleckstrin homology (PH) domain. It is activated by PI3K-generated PIP3, which recruits PDK1 to the plasma membrane. PDK1 phosphorylates the activation loop of AGC kinases (e.g., AKT at Thr308), enabling their full activation. PDK1 also phosphorylates itself at Ser241 for stability. The protein is ubiquitously expressed and essential for embryonic development.
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