Phosphoinositide-dependent kinase-1

PDPK1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1H1W, 1OKY, 1OKZ, 1UU3, 1UU7, 1UU8, 1UU9, 1UVR, 1W1D, 1W1G, 1W1H, 1Z5M, 2BIY, 2PE0, 2PE1, 2PE2, 2R7B, 2VKI, 2XCH, 2XCK, 3H9O, 3HRC, 3HRF, 3ION, 3IOP, 3NAX, 3NAY, 3NUN, 3NUS, 3NUU, 3NUY, 3ORX, 3ORZ, 3OTU, 3PWY, 3QC4, 3QCQ, 3QCS, 3QCX, 3QCY, 3QD0, 3QD3, 3QD4, 3RCJ, 3RWP, 3RWQ, 3SC1, 4A06, 4A07, 4AW0, 4AW1, 4CT1, 4CT2, 4RQV, 4RRV, 4XX9, 5ACK, 5HO7, 5HO8, 5HKM, 5HNG
Identifiers
Aliases	PDPK1, PDK1, PDPK2, PRO0461, PDPK2P, Phosphoinositide-dependent kinase-1, 3-phosphoinositide dependent protein kinase 1
External IDs	OMIM: 605213; MGI: 1338068; HomoloGene: 37643; GeneCards: PDPK1; OMA:PDPK1 - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p13.3 Start 2,537,979 bp[1] End 2,603,188 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 A3.3 Start 24,292,654 bp[2] End 24,369,898 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte middle temporal gyrus Brodmann area 23 bronchial epithelial cell parotid gland caput epididymis corpus epididymis mucosa of sigmoid colon external globus pallidus visceral pleura Top expressed in Rostral migratory stream nucleus accumbens seminiferous tubule ventromedial nucleus zygote pontine nuclei olfactory tubercle anterior amygdaloid area facial motor nucleus epithelium of stomach More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity nucleotide binding protein kinase activity phospholipase binding insulin receptor binding 3-phosphoinositide-dependent protein kinase activity protein serine/threonine kinase activity phospholipase activator activity protein binding ATP binding protein kinase binding kinase activity Cellular component cytoplasm cytosol cell projection membrane focal adhesion plasma membrane nucleoplasm cell junction nucleus perikaryon postsynaptic density cytoplasmic vesicle Biological process intracellular signal transduction regulation of transcription, DNA-templated extrinsic apoptotic signaling pathway negative regulation of protein kinase activity phosphorylation T cell costimulation stimulatory C-type lectin receptor signaling pathway positive regulation of release of sequestered calcium ion into cytosol negative regulation of transforming growth factor beta receptor signaling pathway hyperosmotic response transcription, DNA-templated platelet activation cellular response to epidermal growth factor stimulus Fc-epsilon receptor signaling pathway positive regulation of phospholipase activity protein phosphorylation negative regulation of cardiac muscle cell apoptotic process focal adhesion assembly negative regulation of toll-like receptor signaling pathway peptidyl-serine phosphorylation regulation of endothelial cell migration cellular response to insulin stimulus protein autophosphorylation regulation of mast cell degranulation peptidyl-threonine phosphorylation type B pancreatic cell development T cell receptor signaling pathway cell migration actin cytoskeleton organization regulation of I-kappaB kinase/NF-kappaB signaling calcium-mediated signaling negative regulation of neuron apoptotic process cellular response to brain-derived neurotrophic factor stimulus epidermal growth factor receptor signaling pathway positive regulation of protein localization to plasma membrane activation of protein kinase B activity positive regulation of blood vessel endothelial cell migration positive regulation of angiogenesis positive regulation of vascular endothelial cell proliferation positive regulation of sprouting angiogenesis negative regulation of endothelial cell apoptotic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5170 18607 Ensembl ENSG00000140992 ENSMUSG00000024122 UniProt O15530 Q9Z2A0 RefSeq (mRNA) NM_001261816 NM_002613 NM_031268 NM_001080773 NM_001286662 NM_011062 RefSeq (protein) NP_001248745 NP_002604 NP_112558 NP_001074242 NP_001273591 NP_035192 Location (UCSC) Chr 16: 2.54 – 2.6 Mb Chr 17: 24.29 – 24.37 Mb PubMed search [3] [4]
Wikidata
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In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the PDPK1 gene in humans.^[5] It is implicated in the development and progression of melanomas.^[6]

Function

PDPK1 is a master kinase, which is crucial for the activation of AKT/PKB and many other AGC kinases including PKC, S6K, SGK. An important role for PDPK1 is in the signaling pathways activated by several growth factors and hormones including insulin signaling.

Mice lacking PDPK1 die during early embryonic development, indicating that this enzyme is critical for transmitting the growth-promoting signals necessary for normal mammalian development.

Mice that are deficient in PDPK1 have a ≈40% decrease in body mass, mild glucose intolerance, and are resistant to cancer brought about by hyperactivation of the PI3K pathway (PTEN+/-).^{[7] [8]}

Plant PDK1 plays an important role in regulating PIN-mediated auxin transport, and is thus involved in various developmental processes, such as embryonic development, lateral root formation, vasculature patterning, apical hook formation, gravitropism and phototropism.^[9]

Etymology

PDPK1 stands for 3-phosphoinositide-dependent protein kinase 1. PDPK1 functions downstream of PI3K through PDPK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. However, PDPK1 is believed to be constitutively active and does not always require phosphatidylinositols for its activities.

Phosphatidylinositols are only required for the activation at the membrane of some substrates including AKT. PDPK1 however does not require membrane lipid binding for the efficient phosphorylation of most of its substrates in the cytosol (not at the cell membrane).

Structure

The structure of PDPK1 can be divided into two domains; the kinase or catalytic domain and the PH domain. The PH domain functions mainly in the interaction of PDPK1 with phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate which is important in localization and activation of some of membrane associated PDPK1's substrates including AKT.

The kinase domain has three ligand binding sites; the substrate binding site, the ATP binding site, and the docking site (also known as PIF pocket). Several PDPK1 substrates including S6K and Protein kinase C, require the binding at this docking site. Small molecule allosteric activators of PDPK1 were shown to selectively inhibit activation of substrates that require docking site interaction. These compounds do not bind to the active site and allow PDPK1 to activate other substrates that do not require docking site interaction. PDPK1 is constitutively active and at present, there is no known inhibitor proteins for PDPK1.

The activation of PDPK1's main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDPK1 and AKT at the membrane.

Interactions

Phosphoinositide-dependent kinase-1 has been shown to interact with:

References

Further reading

External links

• 3-phosphoinositide-dependent+protein+kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)