Phosphoinositide-dependent kinase-1

PDPK1
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

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

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

for its activities.

. 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

.

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

with:

References

Further reading

• Vanhaesebroeck B, Alessi DR (2000). "The PI3K-PDK1 connection: more than just a road to PKB". Biochem. J. 346 Pt 3 (3): 561–76.
  PMID 10698680
  .
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4.
  PMID 8125298
  .
• Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997). "Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha". Curr. Biol. 7 (4): 261–9.
  S2CID 2094414
  .
• Moser BA, Dennis PB, Pullen N, Pearson RB, Williamson NA, Wettenhall RE, Kozma SC, Thomas G (1997). "Dual requirement for a newly identified phosphorylation site in p70s6k". Mol. Cell. Biol. 17 (9): 5648–55.
  PMID 9271440
  .
• Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A, Bownes M (1997). "3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase". Curr. Biol. 7 (10): 776–89.
  S2CID 1167390
  .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56.
  PMID 9373149
  .
• Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA (1997). "Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta". J. Biol. Chem. 272 (48): 30491–7.
  PMID 9374542
  .
• Alessi DR, Kozlowski MT, Weng QP, Morrice N, Avruch J (1998). "3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro" (PDF). Curr. Biol. 8 (2): 69–81.
  S2CID 18688785.
• Dalby KN, Morrice N, Caudwell FB, Avruch J, Cohen P (1998). "Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK". J. Biol. Chem. 273 (3): 1496–505.
  PMID 9430688
  .
• Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G (1998). "Phosphorylation and activation of p70s6k by PDK1". Science. 279 (5351): 707–10.
  PMID 9445476
  .
• Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT (1998). "Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B". Science. 279 (5351): 710–4.
  PMID 9445477
  .
• Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR (1998). "Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha". Biochem. J. 331 ( Pt 1) (1): 299–308.
  PMID 9512493
  .
• Anderson KE, Coadwell J, Stephens LR, Hawkins PT (1998). "Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B". Curr. Biol. 8 (12): 684–91.
  S2CID 13936854
  .
• Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ (1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science. 281 (5385): 2042–5.
  PMID 9748166
  .
• Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J (1999). "Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1". Biochem. J. 337 ( Pt 3) (3): 575–83.
  PMID 9895304
  .
• Kobayashi T, Cohen P (1999). "Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2". Biochem. J. 339 ( Pt 2) (2): 319–28.
  PMID 10191262
  .
• Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes CP, Alessi DR (1999). "PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2". Curr. Biol. 9 (8): 393–404.
  S2CID 16473977
  .
• Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA (1999). "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway". EMBO J. 18 (11): 3024–33.
  PMID 10357815
  .
• Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G (1999). "A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans". Genes Dev. 13 (11): 1438–52.
  PMID 10364160
  .
• Casamayor A, Morrice NA, Alessi DR (1999). "Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo". Biochem. J. 342 ( Pt 2) (2): 287–92.
  PMID 10455013
  .

External links

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