PDPK1

Description

The PDPK1 (3-phosphoinositide dependent protein kinase 1) is a protein-coding gene located on chromosome 16.

PDPK1 (3-phosphoinositide-dependent protein kinase-1) is an enzyme encoded by the PDPK1 gene in humans. It is a master kinase crucial for the activation of AKT/PKB and other AGC kinases, including PKC, S6K, and SGK. It plays a significant role in signaling pathways activated by growth factors and hormones, such as insulin signaling. Mice lacking PDPK1 die during embryonic development, highlighting its importance for normal development. Mice deficient in PDPK1 exhibit decreased body mass, glucose intolerance, and resistance to cancer associated with PI3K pathway hyperactivation. In plants, PDK1 regulates auxin transport, affecting developmental processes like embryonic development, root formation, and tropism. PDPK1 functions downstream of PI3K through its interaction with membrane phospholipids, including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate, and phosphatidylinositol (3,4,5)-trisphosphate. PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols, generating phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. However, PDPK1 is thought to be constitutively active and does not always require phosphatidylinositols for its activity.

PDPK1 (3-phosphoinositide-dependent protein kinase 1) is a serine/threonine kinase that acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). PDPK1 plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. PDPK1 negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. PDPK1 activates PPARG transcriptional activity and promotes adipocyte differentiation. PDPK1 activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form of PDPK1 is crucial for the regulation of focal adhesions by angiotensin II. PDPK1 controls proliferation, survival, and growth of developing pancreatic cells. PDPK1 participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. PDPK1 is essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. PDPK1 plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. PDPK1 plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. PDPK1 provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 of PDPK1 is catalytically inactive. PDPK1 exists as a homodimer in its autoinhibited state and is active as a monomer. PDPK1 interacts with NPRL2, PPARG, PAK1, PTK2B, GRB14, PKN1 (via C-terminus), STRAP and IKKB. The Tyr-9 phosphorylated form of PDPK1 interacts with SRC, RASA1 and CRK (via their SH2 domains). PDPK1 interacts with SGK3 in a phosphorylation-dependent manner. The tyrosine-phosphorylated form of PDPK1 interacts with PTPN6. The Ser-241 phosphorylated form of PDPK1 interacts with YWHAH and YWHAQ. PDPK1 binds INSR in response to insulin. PDPK1 interacts (via PH domain) with SMAD3, SMAD4 and SMAD7. PDPK1 interacts with PKN2; the interaction stimulates PDPK1 autophosphorylation, its PI(3,4,5)P3-dependent kinase activity toward 'Ser-473' of AKT1 but also activates its kinase activity toward PRKCD and PRKCZ.

PDPK1 is also known as PDK1, PDPK2, PDPK2P, PRO0461.

Associated Diseases

WES Whole Exome Sequencing

Clinical Exome Sequencing