3 -Phosphoinositide dependent kinase

Feldman RI, Wu JM, Polokoff MA et al. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem 2005 280 19867-74. 

PBKs phosphorylate inositol lipids at the 3 position of the inositol ring to generate the 3-phosphoinositide PI(3,4,5)P3, (PIP3). PBKs of class IB are directly activated by GP t, but others PBK also belong to pathways of receptors with or coupled to tyrosine kinase activity. PIP3 may recruit to tlie membrane various protein kinases, phosphoinositide-dependent kinase-1 (PDK-1), protein kinase B (PKB, or Akt), protein kinase (PKCQ, PLC t and cytosolic tyrosine kinases such as the Bruton s tyrosine kinase (Btk). 

Fig. 12. Some signaling targets and pathways affected by sphingolipid backbones that are metabolically interrelated. PKA, protein kinase A PDKl, 3-phosphoinositide-dependent kinase 1 SDKl, sphingosine-dependent kinase 1 PKC, protein kinase C PPl, protein phosphatase 1 PP2A, protein phosphatase 2A aSMase, acid sphingomyelinase PLA, phospholipase Aj SIP, sphingosine-l-phosphase MATIA, methionine adenosyl-transferase (liver specific) SFl, steroidogenic factor 1. The biophysical properties of ceramides and ceramide 1-phosphates may play important roles in membrane structure, including tendencies to form rafts, membrane curvature, and leakiness.

ABBREVIATIONS APS, adaptor protein with PH and SH2 domains CAP, Cbl associated protein Crkll, chicken tumor virus regulator of kinase II GLUT4, glucose transporter 4 Gab-1, Grb-2 associated binder MAP kinase, mitogen-activated protein kinase PDK, phosphoinositide-dependent kinase PI3 kinase, phosphatidylinositol-3-kinase PIP3, phos-phatidylinositol trisphosphate PKB, protein kinase B (also called Akt) aPKC, atypical isoform of protein kinase C Y, tyrosine residue Y-P, phosphorylated tyrosine residue. 

B and PDKl (phosphoinositide-dependent kinase-1) are recruited to the membrane by their PH domains, where PDKl phosphorylates and activates protein kinase B. Many other signal transducer proteins have PH domains and are docked at the membrane, where they can find and bind each other. Thus, the insulin signal diverges again and again. Insulin is covered in more detail in Chapters 26, 36 and 43. 

Rane, M.J., Coxon, P.Y., Powell, D.W., Webster, R., Klein, J.B., Pierce, W., Ping, P. and McLeish, K.R. (2001). p38 kinase-dependent MAPKAPK-2 acUvation functions as 3-phosphoinositide-dependent kinase-2 for akt in human neutrophils. /. Biol. Chem. 276, 3517-3523. 

Selective 3-phosphoinositide-dependent kinase 1 (PDKl) inhibitors Dissecting the function and pharmacology of PDKl 13JMC2726. Staurosporine analogues from microbial and synthetic sources and their biological activities 13CMD3872. 

PPR-1. Phosphoinositide-dependent kinase-1 is activated by pho hatidylinositol 3,4,5-trisphosphate... 

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