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From CellBiology

Individual Project: Phosphatidylinositol 3-kinase

Introduction

Studies conducted in recent years have shown that phosphoinositides play an important role in signal transduction. The 3-phosphoinositide pathway is one of the two phosphoinositide turnover pathways, and involved in tyrosine-protein kinase-mediated recruitment. This leads to the activation of one of the most important regulatory proteins, Phosphatidylinositol-3 kinase (PI3K), resulting in the production of phosphatidylinositol3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate.[1] PI3K are a family of intracellular transducer enzymes, and are involved in different signaling pathways and the control of key functions of the cells as well as malignant transformation of the cells.[2] PI3K is also involved in motor neuronal diseases due to its role in the tropomyosin-receptor kinase (trk), which belongs to the family of tyrosine-protein kinase receptors.

Structure

Class I, II and III of PI3K domain
PI3Ks are a family of enzymes with three subclasses based on their structure and substrate specificity. They are all composed of 85 kd and 110 kd subunits. The 85 kd subunit (p85α) lacks P13-kinase activity and acts as an adaptor, coupling the 110 kd subunit (p110) to activated protein tyrosine kinases.[3]

Class I

PI3K Class I is a heterodimeric enzyme and known to be receptor-regulated. Class IA consists of 110-kDa catalytic subunits(p110a, p110b or p110d) and associates with an essential 85-kDa (p85) adaptor protein. p85 is important as it interacts with receptor tyrosine kinases. On the other hand, Class IB associates with a p101 adaptor and gets activated by heterotrimeric G-protein subunits.[4]

Class II

PI3K Class II are slightly larger enzymes amongst the subclasses of PI3K and have different structure and function. Three catalytic isoforms of Class II are known to date. Isoforms C2α and C2β can be found in various cells in the body while C2γ is only found in hepatocytes.[3][4]

Class III

Class III were first isolated from mutant yeast strains. However, in later years, it has been identified in other species. Class III are structurally related to the product of the Saccharomyces cerevisiae gene Vps34. It is also structurally similar to Class I as they both exist as a heterodimers of a catalytic (Vps34) and a regulatory (p150) subunits.[4][5]

Function

The involvement of PI3K in intracellular signaling
The ability of PI3K to activate a number of signal proteins including some oncoproteins determines its significance in regulation of cell functions such as growth and survival, aging and malignant transformation.[2] Pl3K is also involved in the control of both malignant cell resistance to mutating agents and the sensitivity of malignant tumors to chemotherapy and radiotherapy.[6] PI3K has an array of main effectors which include the mitogen-transducing signal proteins such as protein kinase C, phosphoinositide-dependent kinases and mitogen activated protein kinases. They are activated either via their interaction with lipid products of PI3K or through PI3K-dependent phosphorylation of proteins.[1] PI3K is activated by number of growth factor receptors with intrinsic and tyrosine kinase activity. These growth factors are platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-l), nerve growth factor (NGF), hepatocyte growth factor (HGF), stem cell growth factor (Steel), and by epidermal growth factor (EGF) in certain cell types.[7][8]

Cell growth control

PI3K plays a critical role in the control of cell division via two possible mechanisms: The PI3K lipid kinase activity and the direct interaction of PI3K with some cellular signal proteins.[6][9] The PI3K lipid kinase activity is involved in protein kinase C activation, which is a mediator of cell division. PKC also occurs via the binding with diacylglycerol formed by hydrolysis of phospholipids.[6] Down-stream processes of PI3K is worth mentioning as it involves the engulfing and degradation of growth receptors. The activated receptor transfer into lysosomes appear to be under PI3K control.[10]

Control of Apoptosis

PI3K plays a rather secondary role in the cell response to stress. Nevertheless, Pl3K is responsible for antiapoptotic signalling and the control of the survival of cells.[10] Over-expression of PI3K in cells produces strong anti-apoptotic effect and causes a significant increase in cell survival. PI3K is a mediator of an activator signal for Serine–threonine protein kinase B (PKB) which possess the ability to prevent apoptosis.[11] PKB interacts with lipid kinases of PI3K followed by the involvement of the protein kinases of PI3K. Studies by Cross et al. revealed that GSK-3 (glycogen synthetase kinase-3) is involved in apoptosis. GSK-3 is phosphorylated by PKB in order to inhibit GSK-3's apoptotic mechanism.[12]

Cell Aging

Morris J, Tissenbaum H, and Ruvkin G conducted experiments which proved that PI3K is involved in the control of aging. Their results have shown that there is a link between Age1, one of the genes of aging, and the gene encoding the PI3K catalytic subunit in mammals.[13] The elements of the anti-apoptotic signaling pathway controlled by PI3K have a crucial role in cell aging. Activation of the anti-apoptotic pathway, especially PKB determines the involvement of PI3K in the control of cell aging.[14]

Malignant Transformation of Cells

The involvement of PI3K in malignant transformation of cells is very important. Some oncoproteins such as abl and T-antigen form complexes with PI3K. In many cancer types, p110 subunit of PI3K Class IA is mutated. This mutation causes the PI3K to be overactive and contributes to cellular transformation and the development of cancer. The changes in cellular signaling pathways often lead to inhibition of apoptosis and increased survival of cells.[14]

Molecular Basis of Disease

Mutation of p110 subunit of PI3K is important in that it becomes the molecular basis of various diseases including malignant transformation of cells and motor neuronal diseases. Mutation of p110 subunit leads to increased cell survival, and inhibits apoptosis. Hence, it leads to accumulation of damaged cells in the body tissues, which eventually interferes with the normal cellular functions.

Current and Recent research

A recent study conducted by Trupti et al. in early 2009 suggests that the activation of Akt by PI3K plays an important role in macrophage mediated response against tumor cells. The PI3K/Akt pathway was found to be required for efficient conjugate formation as well as spreading of macrophages on antibody-coated surfaces. PI3K is also believed to be involved in "the regulation of monocyte/macrophage cytotoxicity through its influence on other protein involved in actin remodeling."[15]

Understanding the mechanism of PI3K in malignant transformation of cells and in signal transduction is also important in developing treatments for diseases related to cell growth and signal transduction. Studies still continue to develop drugs which will one day prove to be useful.

References

  1. 1.0 1.1 Kapeller R, and Cantley LC. Phosphatidylinositol 3-kinase, Bioessays. 1994;16(8):565-76 Cite error: Invalid <ref> tag; name "L1" defined multiple times with different content
  2. 2.0 2.1 Krasilnikov MA. Phosphatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation. Biochemistry. Review 2000;65(1):59-67 Cite error: Invalid <ref> tag; name "L2" defined multiple times with different content
  3. 3.0 3.1 Ian et al., Phosphatidylinositol 3-Kinase: Structure and Expression of the 110 kd Catalytic Subunit. Cell 1992;70:419-429. Cite error: Invalid <ref> tag; name "L3" defined multiple times with different content
  4. 4.0 4.1 4.2 Perisic et al., Structural insights into phosphoinositide 3-kinase catalysis and signaling. Nature. 1999;402:313-320. Cite error: Invalid <ref> tag; name "L4" defined multiple times with different content
  5. Leevers SJ, Vanhaesebroeck B, and Waterfield MD. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Current Opinion in Cell Biology. 1999;11(2):219-25
  6. 6.0 6.1 6.2 Carpenter et al., A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity. Molecular Cell Biology. 1993;13(3):1657–1665. Cite error: Invalid <ref> tag; name "L7" defined multiple times with different content Cite error: Invalid <ref> tag; name "L7" defined multiple times with different content
  7. Stephens LR, Jackson TR and Hawkins PT. Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate: a new intracellular signalling system? Biochim Biophys Acta. 1993;1179(1):27–75.
  8. Hu et al., Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Molecular Cell Biology. 1992;12(3):981–990.
  9. Hiles et al., PI 3-kinase is a dual enzyme: autoregulation by an intrinsic protein-serine kinase activity. Embo Journal. 1994;13:522-533.
  10. 10.0 10.1 Best et al., D-3 phosphoinositide metabolism in cells treated with platelet-derived growth factor. Biochemistry Journal. 1996;319:851–860. Cite error: Invalid <ref> tag; name "L11" defined multiple times with different content
  11. Burgering B, and Coffer P. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995;376:599-602.
  12. Cross et al.,Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785-789.
  13. Morris J, Tissenbaum H, and Ruvkin G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature. 1996;382: 536-539.
  14. 14.0 14.1 Tresini et al. A Phosphatidylinositol 3-Kinase Inhibitor Induces a Senescent-like Growth Arrest in Human Diploid Fibroblasts. Cancer Cancer Research. 1998;58: 1-4. Cite error: Invalid <ref> tag; name "L15" defined multiple times with different content
  15. Trupti et al. The PtdIns 3-Kinase/Akt Pathway Regulates Macrophage-Mediated ADCC against B Cell Lymphoma. PLoS ONE. 2009;4(1):e4208