Phosphoinositide-dependent kinase-1

In the field of is_associated_with::biochemistry, 3-phosphoinositide dependent protein kinase-1, also known as PDPK1 is a is_associated_with::protein which in humans is encoded by the PDPK1 is_associated_with::gene. It is implicated in the development and progression of is_associated_with::melanomas.

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

Etymology
PDPK1 stands for 3- p hosphoinositide- d ependent  p rotein  k inase  1 . PDPK1 functions downstream of is_associated_with::PI3K through PDPK1's interaction with membrane phospholipids including is_associated_with::phosphatidylinositols, is_associated_with::phosphatidylinositol (3,4)-bisphosphate and is_associated_with::phosphatidylinositol (3,4,5)-trisphosphate. is_associated_with::PI3K indirectly regulates PDPK1 by phosphorylating is_associated_with::phosphatidylinositols which in turn generates is_associated_with::phosphatidylinositol (3,4)-bisphosphate and is_associated_with::phosphatidylinositol (3,4,5)-trisphosphate. However, PDPK1 is believed to be constitutively active and does not always require is_associated_with::phosphatidylinositols for its activities.

is_associated_with::Phosphatidylinositols are only required for the activation at the membrane of some substrates including is_associated_with::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 is_associated_with::PH domain. The is_associated_with::PH domain functions mainly in the interaction of PDPK1 with is_associated_with::phosphatidylinositol (3,4)-bisphosphate and is_associated_with::phosphatidylinositol (3,4,5)-trisphosphate which is important in localization and activation of some of membrane associated PDPK1's substrates including is_associated_with::AKT.

The kinase domain has three is_associated_with::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 is_associated_with::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:


 * is_associated_with::AKT1,
 * is_associated_with::PKN2,
 * is_associated_with::PRKACA,
 * is_associated_with::PRKCD,
 * is_associated_with::PRKCI,
 * is_associated_with::Protein kinase Mζ,
 * is_associated_with::Protein kinase N1,
 * is_associated_with::SGK,
 * SLC9A3R2, and
 * is_associated_with::YWHAH