In the field of
biochemistryBiochemistry, 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
proteinProteins 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 geneA 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 kinasePyruvate dehydrogenase kinase is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP....
.)
Function
PDPK1 is a master
kinaseIn 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
AKTAkt, 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
PKCProtein 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,
SGKSerine/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
insulinInsulin 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 pathwayThe 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 -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
and
phosphatidylinositol (3,4,5)-trisphosphatePhosphatidylinositol -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)-bisphosphatePhosphatidylinositol -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
and
phosphatidylinositol (3,4,5)-trisphosphatePhosphatidylinositol -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
AKTAkt, 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 -bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger...
and
phosphatidylinositol (3,4,5)-trisphosphatePhosphatidylinositol -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
AKTAkt, 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
ligandIn 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 CProtein 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 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
SGKSerine/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....
,
PRKACAcAMP-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 2Sodium-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...
,
PRKCDProtein 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,
PKN2Serine/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:...
,
PRKCIProtein 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 N1Serine/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:...
,
YWHAH14-3-3 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
AKT1RAC-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 :...
.