Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase B (PKB) is a serine/threonine kinase that is activated by growth hormones and implicated in prevention of apoptosis, glycogen metabolism, and glucose uptake. A key enzyme in PKB activation is phosphatidylinositide 3-kinase (PI-3K), which triggers the dual phosphorylation of PKB by phosphatidylinositol-dependent kinases (PDKs). Here we report that the major PKB subtype in platelets is PKBalpha, which is activated by phosphorylation of Thr(308) and Ser(473) and has a constitutively phosphorylated Thr(450) that does not contribute to PKB activation. alpha-Thrombin and thrombopoietin activate PKBalpha via PI-3K and trigger the concurrent phosphorylation of Thr(308) (via PDK1) and Ser(473) (via a not yet identified PDK2). In addition, alpha-thrombin activates a PI-3K-independent pathway involving phospholipase Cbeta and calcium-dependent protein kinase C subtypes (PKCalpha/beta). This route is specific for phosphorylation of Ser(473) and can be initiated by direct PKC activation with phorbol ester or purified active PKC catalytic fragment in platelet lysate. Different degrees of Ser(473) and Thr(308) phosphorylation correlate with different degrees of enzyme activity. These data reveal a PI-3K-independent PKB activation in which PKCalpha/beta regulates the phosphorylation of Ser(473) in PKBalpha. The independent control of the two phosphorylation sites may contribute to fine regulation of PKBalpha activity.
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PMID:Dual regulation of platelet protein kinase B. 1087 27

Excessive reactive oxygen species (ROS) are toxic to hematopoietic cells. The majority of cellular ROS are derived from mitochondria and glucose metabolism, and cytokines stimulate this process. During hypoxia, hypoxia inducible factor-1 (HIF-1) attenuates hypoxia-induced mitochondrial ROS production through the induction of pyruvate dehydrogenase kinase-1 (PDK-1). Previously, we found that thrombopoietin (TPO) induces the generation of mitochondrial ROS. Interestingly, the TPO-induced production of mitochondrial ROS promotes the activation of HIF-1. Based on these findings, we speculated that TPO-activated HIF-1 functions as a feedback mechanism to block the overproduction of ROS following TPO stimulation. We found that TPO induces the expression of PDK-1 in a TPO-dependent cell line, UT-7/TPO, in a HIF-1-dependent manner. Inhibition of either HIF-1 or PDK-1 resulted in the increased production of ROS following TPO stimulation. Our observations suggest that HIF-1 functions as a ROS sensor to prevent the overproduction of mitochondrial ROS following cytokine stimulation.
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PMID:HIF-1 prevents the overproduction of mitochondrial ROS after cytokine stimulation through induction of PDK-1. 1965 31