Phosphoinositide-dependent kinase-1

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]

Not to be confused with Pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1).
PDPK1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPDPK1, PDK1, PDPK2, PRO0461, PDPK2P, Phosphoinositide-dependent kinase-1, 3-phosphoinositide dependent protein kinase 1
External IDsOMIM: 605213 MGI: 1338068 HomoloGene: 37643 GeneCards: PDPK1
Orthologs
SpeciesHumanMouse
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 MbChr 17: 24.29 – 24.37 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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
  1. GRCh38: Ensembl release 89: ENSG00000140992 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000024122 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: PDPK1".
  6. Scortegagna M, Ruller C, Feng Y, Lazova R, Kluger H, Li JL, De SK, Rickert R, Pellecchia M, Bosenberg M, Ronai ZA (2014). "Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma". Oncogene. 33 (34): 4330–9. doi:10.1038/onc.2013.383. PMC 3955742. PMID 24037523.
  7. Mora A, Komander D, van Aalten DM, Alessi DR (April 2004). "PDK1, the master regulator of AGC kinase signal transduction". Semin. Cell Dev. Biol. 15 (2): 161–70. doi:10.1016/j.semcdb.2003.12.022. PMID 15209375.
  8. Frödin M, Antal TL, Dümmler BA, Jensen CJ, Deak M, Gammeltoft S, Biondi RM (October 2002). "A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation". EMBO J. 21 (20): 5396–407. doi:10.1093/emboj/cdf551. PMC 129083. PMID 12374740.
  9. Tan, Shutang; Zhang, Xixi; Kong, Wei; Yang, Xiao-Li; Molnár, Gergely; Vondráková, Zuzana; Filepová, Roberta; Petrášek, Jan; Friml, Jiří; Xue, Hong-Wei (2020). "The lipid code-dependent phosphoswitch PDK1–D6PK activates PIN-mediated auxin efflux in Arabidopsis". Nature Plants. 6 (5): 556–569. doi:10.1038/s41477-020-0648-9. PMID 32393881. S2CID 218593545.
  10. Barry FA, Gibbins JM (April 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem. 277 (15): 12874–8. doi:10.1074/jbc.M200482200. PMID 11825911.
  11. Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP, Dedhar S (July 2001). "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343". J. Biol. Chem. 276 (29): 27462–9. doi:10.1074/jbc.M102940200. PMID 11313365.
  12. Hodgkinson CP, Sale GJ (January 2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry. 41 (2): 561–9. doi:10.1021/bi010719z. PMID 11781095.
  13. Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR (July 2000). "A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta ) and PKC-related kinase 2 by PDK1". J. Biol. Chem. 275 (27): 20806–13. doi:10.1074/jbc.M000421200. PMID 10764742.
  14. Biondi RM, Cheung PC, Casamayor A, Deak M, Currie RA, Alessi DR (March 2000). "Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA". EMBO J. 19 (5): 979–88. doi:10.1093/emboj/19.5.979. PMC 305637. PMID 10698939.
  15. Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA (June 1999). "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway". EMBO J. 18 (11): 3024–33. doi:10.1093/emboj/18.11.3024. PMC 1171384. PMID 10357815.
  16. Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ (September 1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science. 281 (5385): 2042–5. doi:10.1126/science.281.5385.2042. PMID 9748166.
  17. Chun J, Kwon T, Lee E, Suh PG, Choi EJ, Sun Kang S (October 2002). "The Na(+)/H(+) exchanger regulatory factor 2 mediates phosphorylation of serum- and glucocorticoid-induced protein kinase 1 by 3-phosphoinositide-dependent protein kinase 1". Biochem. Biophys. Res. Commun. 298 (2): 207–15. doi:10.1016/s0006-291x(02)02428-2. PMID 12387817.
  18. Sato S, Fujita N, Tsuruo T (October 2002). "Regulation of kinase activity of 3-phosphoinositide-dependent protein kinase-1 by binding to 14-3-3". J. Biol. Chem. 277 (42): 39360–7. doi:10.1074/jbc.M205141200. PMID 12177059.

Further reading
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