In the field of
biochemistry
Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, a ...
, PDPK1 refers to the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
3-phosphoinositide-dependent protein kinase-1, an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
which is encoded by the ''PDPK1''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
in humans.
It is implicated in the development and progression of
melanoma
Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...
s.
Function
PDPK1 is a master
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
, which is crucial for the activation of
AKT/PKB and many other
AGC kinase
AGC may refer to:
Organizations
In business
* AGC Inc. (formerly Asahi Glass Co.), a glass manufacturer
* Associated General Contractors of America, an association of commercial construction contractors
* Australian Guarantee Corporation, a fi ...
s including
PKC,
S6K,
SGK. An important role for PDPK1 is in the signaling pathways activated by several growth factors and hormones including
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
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
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
through PDPK1's interaction with membrane phospholipids including
phosphatidylinositols,
phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)''P''2) is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)''P''2 at the plasma membrane activates a number of important cell sig ...
and
phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...
.
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
indirectly regulates PDPK1 by phosphorylating
phosphatidylinositols which in turn generates
phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)''P''2) is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)''P''2 at the plasma membrane activates a number of important cell sig ...
and
phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...
. 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
Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.
This domain can bind phosph ...
. The
PH domain
Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton.
This domain can bind phosph ...
functions mainly in the interaction of PDPK1 with
phosphatidylinositol (3,4)-bisphosphate
Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)''P''2) is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)''P''2 at the plasma membrane activates a number of important cell sig ...
and
phosphatidylinositol (3,4,5)-trisphosphate
Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...
which is important in localization and activation of some of membrane associated PDPK1's substrates including
AKT.
The kinase domain has three
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
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
In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
, 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
RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It ...
,
*
PKN2
Serine/threonine-protein kinase N2 is an enzyme that in humans and ''Strongylocentrotus purpuratus'' is encoded by the ''PKN2'' gene.
Interactions
PKN2 has been shown to interact with:
* AKT1,
* NCK1,
* PTPN13,
* Phosphoinositide-depend ...
,
[
* ]PRKACA
The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the ''PRKACA'' gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catal ...
,
* PRKCD
Protein kinase C delta type (or PKC-δ) is an enzyme that in humans is encoded by the ''PRKCD'' gene.
Function
Protein kinase C (PKC) is a family of serine- and threonine-specific protein kinases that can be activated by the second messeng ...
,
* PRKCI
Protein kinase C iota type is an enzyme that in humans is encoded by the ''PRKCI'' gene.
Function
This gene encodes a member of the protein kinase C (PKC) family of serine/threonine protein kinases. The PKC family comprises at least eight memb ...
,[
* ]Protein kinase Mζ
Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein in humans that is encoded by the ''PRKCZ'' gene. The PRKCZ gene encodes at least two alternative transcripts, the full-length PKCζ and an N-terminal truncated form PKMζ. PKMζ ...
,
* Protein kinase N1
Serine/threonine-protein kinase N1 is an enzyme that in humans is encoded by the ''PKN1'' gene.
Function
The protein encoded by this gene belongs to the protein kinase C superfamily. This kinase is activated by Rho family of small G proteins ...
,[
* SGK,]
* SLC9A3R2,[ and
* ]YWHAH
14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the ''YWHAH'' gene.
Function
This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate si ...
References
Further reading
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
External links
*
{{Portal bar, Biology, border=no
Protein kinases
EC 2.7.11