Phosphoinositide-dependent kinase-1
Encyclopedia
In the field of biochemistry
, 3-phosphoinositide dependent protein kinase-1, also known as PDPK1 is a protein
which in humans is encoded by the PDPK1 gene
.
PDPK1 is also known as "PDK1" ("PDK" can be confused with pyruvate dehydrogenase 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 signalling pathways activated by several growth factors and hormones including insulin
signalling.
Mice lacking PDPK1 die during early embryonic development, indicating that this enzyme is critical for transmitting the growth-promoting signals nescessary 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+/-).
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 is 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).
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.
with SGK
, PRKACA
, Sodium-hydrogen exchange regulatory cofactor 2
, PRKCD
, Protein kinase Mζ, PKN2
, PRKCI
, Protein kinase N1
, YWHAH
and AKT1
.
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, 3-phosphoinositide dependent protein kinase-1, also known as PDPK1 is a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the PDPK1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
PDPK1 is also known as "PDK1" ("PDK" can be confused with pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase
Pyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP....
.)
Function
PDPK1 is a master kinaseKinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
, which is crucial for the activation of AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
/PKB and many other AGC kinases including PKC
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
, S6K, SGK
SGK
Serine/threonine-protein kinase SGK is a kinase subfamily that is currently known as being encoded by SGK1, SGK2, and SGK3 genes.The SGK1 kinase regulates the myo-inositol transporter during osmotic stress....
. An important role for PDPK1 is in the signalling pathways activated by several growth factors and hormones including insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
signalling.
Mice lacking PDPK1 die during early embryonic development, indicating that this enzyme is critical for transmitting the growth-promoting signals nescessary 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
PI3K/AKT/mTOR pathway
The PI3K/AKT/mTOR pathway is an intracellular signalling pathway important in apoptosis and hence cancer e.g. breast cancerand non-small-cell lung cancer.]PI3K activation activates AKT which activates mTOR....
(PTEN+/-).
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)-bisphosphatePhosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
and phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
. PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
and phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
. However, PDPK1 is believed to be constitutively active and does not always require phosphatidylinositols for its activities.
Phosphatidylinositols is only required for the activation at the membrane of some substrates including AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
. 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)-bisphosphatePhosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
and phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
which is important in localization and activation of some of membrane associated PDPK1's substrates including AKT
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
.
The kinase domain has three ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
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
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
, 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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with SGK
SGK
Serine/threonine-protein kinase SGK is a kinase subfamily that is currently known as being encoded by SGK1, SGK2, and SGK3 genes.The SGK1 kinase regulates the myo-inositol transporter during osmotic stress....
, PRKACA
PRKACA
cAMP-dependent protein kinase catalytic subunit alpha is an enzyme that in humans is encoded by the PRKACA gene.-Interactions:PRKACA has been shown to interact with Phosphoinositide-dependent kinase-1, IQGAP1, KvLQT1 and Ryanodine receptor 2....
, Sodium-hydrogen exchange regulatory cofactor 2
Sodium-hydrogen exchange regulatory cofactor 2
Sodium-hydrogen exchange regulatory cofactor NHE-RF2 also known as tyrosine kinase activator protein 1 or SRY-interacting protein 1 is a protein that in humans is encoded by the SLC9A3R2 gene.NHERF-2) is a scaffold protein that connects plasma membrane proteins with members of the...
, PRKCD
PRKCD
Protein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.- Function :Protein kinase C is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol...
, Protein kinase Mζ, PKN2
PKN2
Serine/threonine-protein kinase N2 is an enzyme that in humans is encoded by the PKN2 gene.-Interactions:PKN2 has been shown to interact with Phosphoinositide-dependent kinase-1, AKT1, NCK1, PTPN13 and RHOA.-Further reading:...
, PRKCI
PRKCI
Protein kinase C iota type is an enzyme that in humans is encoded by the PRKCI gene.-Interactions:PRKCI has been shown to interact with Glyceraldehyde 3-phosphate dehydrogenase, Centaurin, alpha 1, Phosphoinositide-dependent kinase-1, FRS2, SMG1 , Sequestosome 1 and PARD3.-Further reading:...
, Protein kinase N1
Protein kinase N1
Serine/threonine-protein kinase N1 is an enzyme that in humans is encoded by the PKN1 gene.-Interactions:Protein kinase N1 has been shown to interact with Phospholipase D1, Phosphoinositide-dependent kinase-1, Vimentin, AKAP9, CCDC85B, Actinin, alpha 1, NEFL, NEUROD2 and RHOA.-Further reading:...
, YWHAH
YWHAH
14-3-3 protein eta is a protein that in humans is encoded by the YWHAH gene.-Interactions:YWHAH has been shown to interact with TNFAIP3, KLC3, C-Raf, Phosphoinositide-dependent kinase-1, RIMS2, KIF5B, RIMS1, CDC25B, ZFP36, EPB41L3, Glucocorticoid receptor and TLX2.-Further reading:...
and AKT1
AKT1
RAC-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. Multiple alternatively spliced transcript variants have been found for this gene.- Function :...
.