What is PDK1 activated by?
PDK1 was identified as the upstream activation loop kinase of protein kinase Bα (PKBα; also known as Akt1), which is essential for the activation of PKB (1, 39, 42). PDK1 interfaces with each of these cell regulatory networks through kinases such as PKB and therefore could be a point of therapeutic intervention.
How many proteins are targeted by phosphorylation?
Phosphorylation alters the structural conformation of a protein, causing it to become activated, deactivated, or modifying its function. Approximately 13000 human proteins have sites that are phosphorylated.
What does protein kinase a target?
Phosphorylation Targets The catalytic subunits of protein kinase A phosphorylate proteins at serine and threonine residues; the usual target sequence is [Arg-Arg-X-Ser/Thr-X], where X is a hydrophobic amino acid. Protein kinase A phosphorylates substrates in both the cytoplasm and nucleus.
What does PDK1 stand for?
PDK1 (3-Phosphoinositide-dependent kinase 1) is a key member of the AGC protein kinase family. It plays an important role in a variety of cellular functions, leading to the activation of the PI3K signaling pathway, an event often associated with the onset and progression of several human cancers.
How does PIP3 activate PDK1?
PIP3 formation is negatively regulated by the PTEN tumor suppressor protein, a phosphatase that dephosphorylates PIP3 and coverts it to PIP2. PIP3 recruits AKT and PDK1 to the plasma membrane, enabling the PDK1 to phosphorylate AKT on a conserved threonine residue.
Is PDK1 an enzyme?
The human PDK1 is a 556-residue monomeric enzyme comprising of a catalytic domain that is most similar to the PKA, PKB and PKC subfamily of protein kinases.
Where does phosphorylation of proteins take place?
Mechanism of phosphorylation. While phosphorylation is a prevalent post-translational modification (PTM) for regulating protein function, it only occurs at the side chains of three amino acids, serine, threonine and tyrosine, in eukaryotic cells.
Does PIP3 bind to PDK1?
The PI3K product PIP3 serves as an anchor for the recruitment of downstream effectors, including PDK1 and Akt.
What is the role of PDK1 in cancer?
An increasing amount of evidence hints at 3-phosphoinositide dependent protein kinase-1 (PDK1 or PDPK1) as an intriguing and underexplored target for cancer therapy. Several reports show that PDK1 expression is dysregulated in multiple cancer types.
Which is the prototypical activity of PDK1?
The prototypical PDK1 activity is the phosphorylation of protein kinases of AGC or related families on the activation loop, eliciting their activation [16]. From a structural viewpoint, PDK1 is a soluble and globular medium-sized protein constituted by only two domains, an N-terminal kinase domain and a C-terminal PH domain [2] ( Fig. 1 C).
Which is phosphoinositide dependent kinase 1 ( PDK1 )?
3-Phosphoinositide-dependent kinase 1 (PDK1) has been identified as the activating kinase that phosphorylates PKB in a PI 3-kinase dependent process at Thr 308 in vitro and in vivo (see Fig. 1 ).
Where does PDK1 belong in the AGC family?
PDK1 belongs to the AGC family of kinases and was originally isolated as the kinase that catalyzes the AL phosphorylation of PKB in mammalian cells. D. discoideum cells have two PDK orthologues, PDKA and PDKB, that contain a kinase domain and a C-terminal PH domain.