Phosphoinositide-dependent kinase-1

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+/-).

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.

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:

• AKT1,
• PKN2,
• PRKACA,
• PRKCD,
• PRKCI,
• Protein kinase Mζ,
• Protein kinase N1,
• SGK,
• SLC9A3R2, and
• YWHAH

References

References

1. "Entrez Gene: PDPK1".
2. (2014). "Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma". Oncogene.
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4. (October 2002). "A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation". EMBO J..
5. (2020). "The lipid code-dependent phosphoswitch PDK1–D6PK activates PIN-mediated auxin efflux in Arabidopsis". Nature Plants.
6. (April 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem..
7. (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..
8. (March 2000). "Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA". EMBO J..
9. (January 2002). "Regulation of both PDK1 and the phosphorylation of PKC-zeta and -delta by a C-terminal PRK2 fragment". Biochemistry.
10. (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..
11. (September 1998). "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science.
12. (June 1999). "Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway". EMBO J..
13. (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..
14. (October 2002). "Regulation of kinase activity of 3-phosphoinositide-dependent protein kinase-1 by binding to 14-3-3". J. Biol. Chem..