Phosphoinositide 3-Kinases

Phosphoinositide 3-Kinases catalyze the phosphorylation of of Phosphotidylinositols, changing them into Phosphoinositols by phosphorylating the inositol ring's free OH groups. In this way, Phosphoinositide 3-Kinases plays a key enzymatic role in production of phosphoinositol 3,4,5-trisphosphate. Activated PI3-K converts plasma membrand lipid Phosphoinositol-4,5-bisphosphate [PI(4,5)P2] into Phosphinositol-3,4,5-trisphosphate [PI(3,4,5)P3]. There are multiple isoforms of PI3-K which can be divided into three main classes: Class I, II and III. Class I is further devided into IA and IB. Class IA and IB are the enzymes primarily reponsible for D-3-phosphoinositides. these enzymes are heterodimers of regulatory and catalytic subunits. Both isoforms contain the subunit p110.The binding of p110 to the enzyme RAS which is induced by growth factor stimulates PI3-K activity (See Figure 9). Pleckstrin Homology domains allow certain proteins, most notably Protein Kinase B (PKB) and Phosphoinositide-dependant kinase 1 (PDK-1), to bind to [PI(3,4,5)P3] and in this manner, they accumulate at sites of PI3-K activity. By binding to [PI(3,4,5)P3], PDK-1 and PKB come into close enough contact that PDK-1 can phosphorylate PKB. The subsequent activation of PKB is a key step in many metabolic pathways. While PI3-K is involved in numerous metabolic protein cascades which affect cell growth and survival, it is also tied to such human diseases as diabetes and cancer.

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• Class I: Class I PI3-K are heterodimers made up of a 110kDa catalytic subunit and an adaptor/ regulation subunit. this class is divided into two subclasses. IA which signals down stream of tyrosine kinases and IB which signal down strem of herterotrimeric G-protein coupled receptors. These are largely cytosolic proteins.
  • IA PI3K's p110 shares a comlex with two Src-homologous-2 domains which are believed to be the portion of the protein which allows PI3K to move from the cytosol to the membrane where its p110 can bind to PAS and where [PI(4,5)P2] resides. There are several p110 isoforms found for the IA p110 subunits: p110 a, b, g and at least seven adaptor/regulation subunit isoforms including the p85 a, b, and g.
    
  • There is currently only one identified IB identified: p110 delta which is complexed with a p101 adaptor protein. This isoform is abundant only in white blood cells.
    
• Class II: Class II PI3-K is a p170 molecule. It's unique feature is a C-terminal C2 domain. Because this C2 domain lacks a certain aspartate residue, it is capable of binding to phospholipids in vitro without the presence of the Calcium 2 ion. This makes the Class II PI3-K protein a unique one. These proteins are predominately found in the membrane of cells and are activated by such things as insulin, epidermal growth factor, and platelet-derived growth factor.
  
• Class III: Class III PI3-Ks are the homologs of a yest vesicular protein-sorting protein. There is no variation of the catalytic unit between species. The Ser/Thr p150 protein kinase is the same in all organisms from yeast to mammals.

  
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