Phosphoinositide 3-Kinases

This page, as it appeared on November 15, 2010, was featured in this article in the journal Biochemistry and Molecular Biology Education.

spinqualitylabelsall models PI3K (grey) complex with NISH2 P85α and wortmannin (PDB code 3hhm) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D PI3K p110α Subunit, 3hhm Function Phosphoinositide 3-Kinases or phosphatidylinositol 3-kinase (PI3K) are a family of ubiquitously distributed lipid kinases, that play a critical role in the regulation of numerous cellular processes including cellular growth and morphology, programmed cell death, cell motility and adhesion, mitogenesis and glucose uptake. PI3K generates important second messengers by catalyzing the transfer of the γ-phosphate group of ATP to the D3 position of phosphoinositides. The PI3K preferred substrate is Phosphatidylinositol-4,5-bisphosphate (PIP2), which is converted into phosphatidylinositol-3,4,5-triphosphate (PIP3) upon phosphorylation at the cell membrane. The importance of PI3K is evident in knockout mice studies in which those mice with disruptions of critical PI3K components have significant deficiencies in immune and inflammatory response sometimes resulting in embryonic death. Aberrations in PIP3 levels, either through activation of PI3ks or through inactivation of lipid phosphatase PTEN, occur frequently in numerous forms of cancer, making PI3K an exciting new target to treat cancer among other human diseases. For additional details see PI3K Activation, Inhibition, & Medical Implications Human PI3K p110alpha/p85alpha The Structure of PI3K Akt/PKB signaling pathway Diabetes & Hypoglycemia. The Classes of PI3Ks Signal Transduction Pathway. PI3K Highlighted in Red. Click to Expand PI3Ks can be grouped into three distinct classes, Class I-III. Class I PI3Ks, the most well understood and thoroughly explored PI3K class, are composed of a 110kDa catalytic subunit and a 50-100 kDa adaptor subunit. Activation of Class I PI3Ks is controlled by extracellular signaling via receptors with intrinsic tyrosine kinase activity, G protein-linked receptors, or receptors coupled to SRC like protein tyrosine kinases. Class II PI3Ks are relatively poorly understood but are 170-210 kDa and have in vitro substrate specificity toward PtdIns 4-P. Class III PI3Ks depend on Vps15p protein Ser/Thr kinases, which recruits the phosphatidylinositol kinase to late Golgi Compartments. Class I Subclasses PI3Ks are activated by extracellular agonists via the translocation of PI3Ks to the plasma membrane for easy access to lipid substrates. Depending on the adaptor proteins involved in the process, Class I PI3Ks are segregated into two subgroups. Those that associate with p85 will be directed to phosphorylated tyrosine motifs (Class IA), Phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3Kγ) catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol-4, 5-bisphosphate and ATP to 1-phosphatidyl-1D-myo-inositol-4, 5-trisphosphate. PI3Kγ interacts with trimeric G proteins and the p101 protein (Class IB) Structure of PI3K For Full Article, See: The Structure of PI3K Class I PI3Ks, which are tightly regulated by tyrosine kinases, are composed of an 85kDa regulatory/adapter subunit (p85) and a 110kDa catalytic subunit (p110). PI3K Activation, Inhibition, and Medical Implications For Full Article, See: PI3K Activation, Inhibition, & Medical Implications A number of inhibitors for PI3K have been developed to understand how PI3K is activated and functions. These analysis have massive medical implications for the treatment of Cancer and Diabetes. Inhibitors of Type I PI3K p110γ and Type I PI3K p110δ are tested as therapeutic drugs against inflammatory etiologists . 3D Structures of PI3K Phosphoinositide 3-kinase 3D structures

Additional Resources

• See: 3hhm For Additional Proteins involved in the disease.
  
• See: PTEN for Additional examples of oncogenes and tumor suppressor genes.

Proteopedia Page Contributors and Editors (what is this?)

David Canner, Angel Herraez, Jaime Prilusky, Hannah Campbell, Joel L. Sussman, Alexander Berchansky, Michal Harel