Class II

Ptdlns(4)P Ptdlns

Fig. 1. The phosphoinositide (PI3-K) superfamily. Schematic representation of the modular structure of PI3-K catalytic and regulatory subunits (adapted from refs. 1,106). In vitro substrates for each class of PI3-K are shown in italics. The adaptor subunit p85a is shown. The domain structure of p85P is similar; p55a, p50a, and p55y are shorter forms consisting of the SH2 domains and inter-SH2 domain alone. Class IA heterodimer formation is mediated by interactions between the N-terminal region of the catalytic subunit (P85BD) and the inter-SH2 domain of the adaptor subunit. Class IB heterodimer protein-protein interactions are less well defined and occur in multiple regions. HR, homology region; P85BD, P85 Binding domain; SH3, Src homology 3 domain; SH2, Src homology 2 domain; GAP, RhoGAP domain; CC, Coiled-coil region; Pro, Proline rich region; PX, Phox domain; C2, C2 domain.

Class III

Ptdlns tors, e.g., growth factor receptors, or indirectly by adaptor molecules such as Shc, growth factor receptor bound protein, (Grb2) or insulin receptor substrate (IRS)-1 (2). P1105 was originally identified in leukocytes but is also expressed in other cell types including breast tissue and melanocytes (3). The p110a and p110P isoforms are ubiquitous. Class IB consists of one member, a heterodimer of p110y and a regulatory subunit termed p101, and is activated by G protein Py subunits following the stimulation of G protein-coupled receptors (GPCRs). The expression of p110y is predominantly in leukocytes but this isoform is also found in cardiac tissue. Both class IA and IB catalyze the formation of PtdIns

(3,4,5)P3 in vitro and in addition to regulation by cell surface receptors, they can be activated directly by the small GTPase, Ras (4). Class II consists of three isoforms, PI3-K-C2a, P, and y, which phosphorylate PtdIns and PtdIns (4)P in vitro. PI3-K-C2a and P are widely expressed whereas PI3-K-C2y is restricted to liver, breast, and prostate. More recently, a systematic immunohistochemical analysis has revealed the differential expression of PI3-K-C2a and C2P in smooth muscle and peripheral nerves respectively (5). Class II PI3-Ks are predominantly associated with both plasma membrane and intracellular membrane compartments and their mechanism of regulation is not well understood. Recent evidence has indicated that clathrin functions as an adaptor for PI3-K-C2a, binding to its N-terminal region and stimulating its activity. In addition, the activation of Class II enzymes by growth factors (6,7) and the chemokine MCP-1 (8) has been reported. The class III PI3-K displays a high degree of homology to the yeast vacuolar sorting protein, VPS34, and utilizes PtdIns as a substrate. The mammalian enzyme controls the maturation of phagosomes (9) and also plays a role in vesicular transport (10). Finally, a number of other kinases (mTOR, DNA-PK, ATM, SMG-1) are distantly related to the PI3-Ks; but as these enzymes do not phosphorylate inositol lipids, they will not be detailed further.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment