Non-receptor Kinases & Phosphatases
PI3K
The phosphoinositide 3-kinase (PI3K) enzymes regulate several key signal transduction pathways controlling vital cell processes that are implicated in carcinogenesis. LICR investigators are studying the different PI3K enzymes and their targets, and developing drugs that specifically inhibit the different forms of PI3K for potential cancer therapies.
Introduction
The phosphoinositide 3-kinase (PI3K) family is a group of enzymes that generate lipid 'second messengers' that mediate signal transduction. PI3K signaling initiates normal cell processes that are frequently disrupted by carcinogenesis: growth, differentiation (the structure and/or function of a cell is changed), survival, proliferation, migration, metabolism, and metastasis. The first human PI3K genes were isolated and cloned by LICR teams at the London University College Branch. LICR investigators also isolated the PI3K genes from the fruit fly, Drosphila, allowing the use of this model system in revealing the intricacies of the PI3K signaling pathways.
In addition to cancer, PI3K signaling has also been implicated in angiogenesis, the formation of new blood vessels, which itself contributes to tumor growth and cancer spread (see Angiogenesis Program), and perturbations in: the immune system; insulin signaling; glucose homeostasis (control of glucose levels); and fat metabolism. Disruptions of the latter three factors are thought to lead to Type II diabetes, which affects 5-10% of the world’s population.
The PI3K Family
Some years ago, LICR investigators classified the various forms of PI3K based on the structure and function of each enzyme; this categorization is now the international convention for classifying PI3Ks. Class IA enzymes consist of any one of the 'catalytic' subunits (p110α , p110β, or p110δ) complexed with any one of the 'regulatory' subunits (p85α, p85β or p55γ). Only one Class IB PI3K enzyme exists, and is made up of the p110γ catalytic and the p101 regulatory subunit. There are also three Class II PI3Ks (CIIα, CIIβ, and CIIγ) and one Class III PI3K (Vps34).
PI3K Signal Transduction
Signaling from the Class I PI3Ks (more...)
The Class IA enzymes are activated by tyrosine kinases (e.g. growth factor receptors), antigen receptors, and cytokine receptors, whilst the Class IB enzyme is activated by 'G Protein Coupled Receptors' (GPCRs). Class II PI3Ks are thought to be activated by some tyrosine kinase receptors, GPCRs, integrins, and chemokines. The Class III PI3K appears to be constitutively activated.
In response to activation, each PI3K generates a specific lipid second messenger, which binds to, and activates, specific proteins in distinct signal transduction pathways. The signal transduction pathways remain active until phosphatase enzymes, in particular the oncogene PTEN, dephosphorylate the PI3K lipid second messengers.
PI3K and Cancer
Many of the known tumor suppressor genes and oncogenes are components of, or regulate, signaling pathways involving PI3Ks. Increased PI3K signaling results in an accumulation of lipid second messengers that inappropriately stimulate signal transduction pathways and lead to cell transformation (of a normal cell into a cancerous cell).
The deregulation of PI3K signaling is thought to occur in two different ways. The first is an increase in PI3K signaling resulting from activating gene mutations, amplification (an increased number of gene copies) and overexpression (an increased number of protein copies) of PI3Ks or upstream receptors that activate PI3Ks. For example, mutations that activate the epidermal growth factor receptor (EGFR), which is commonly overexpressed in cancer, have been shown to increase the levels of the PI3K lipid products. PI3Ks are also activated by the oncogene Ras, which is mutated in approximately 25% of all human cancers. It has been shown that Ras-dependent PI3K activation is essential for several cell processes necessary for cell transformation.
Loss of the tumor suppressor, the phosphatase PTEN, which occurs in many aggressive brain tumors, endometrial and breast cancers, and melanomas, is the second mechanism of PI3K deregulation. In fact, investigators at the LICR San Diego Branch were the first to show that PTEN was able to suppress the growth of human tumor cells.The loss of PTEN, either by deletion of the gene or by deactivating mutations, is one of the most common lesions in cancer, and causes constitutive PI3K signaling through the build up of PI3K lipid products.
PI3K and Immunology
The p110δ and p110γ isoforms differ from the other PI3K subunits in that they have a 'tissue-restricted expression'. The p110γ isoform is expressed only in white blood cells, whilst p110δ is expressed in white blood cells, breast tissue, and melanocytes. The expression of p110δ in white blood cells led one LICR team to investigate PI3K signaling in immunity. By specifically deactivating the p110δ PI3K, the team was able to show that PI3K signaling plays an important role in the development and function of B and T lymphocytes. These results, taken with results from other investigators, suggest that too much PI3K activity could lead to autoimmunity and leukemia, whilst a reduction in PI3K activity could lead to immunodeficiency. Recently, LICR investigators found that p110d plays an essential role in the allergic response. Inactivation of p110d appears to protect against anaphylactic (allergic) responses, thus p110d may be a new target for allergy therapies.
PI3K Inhibitors
LICR, in collaboration with the Yamanouchi Pharmaceutical Company Ltd (Japan), Cancer Research UK (UK), and the Institute for Cancer Research (UK), has developed first-generation isoform-specific PI3K small molecule inhibitors. Given the central role of PI3K signaling in cancer, these inhibitors may prevent tumor growth by stopping the proliferation and growth of tumor cells.
Additional research from LICR has shown that a p110 -specific inhibitor is able to prevent the migration of transformed breast cancer cells that overexpress EGFR. Thus p110δ inhibitors may be of use as anti-metastatic therapies (to limit cancer spread) in some breast cancers.
Finally, as a consequence of LICR findings of PI3K signaling involvement in immunology, it is thought that PI3K inhibitors might also be of use to prevent organ transplant rejection and certain autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.
Key Publications
- K. Ali, A. Bilancio, M. Thomas, W. Pearce, A.M. Gilfillan, C. Tkaczyk, N. Kuehn, A. Gray, J. Giddings, E. Peskett, R. Fox, I. Bruce, C. Walker, C. Sawyer, K. Okkenhaug, P. Finan, and B. Vanhaesebroeck. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature. 431(7011):1007-11, 2004.
- K. Okkenhaug and B. Vanhaesebroeck. PI3K in lymphocyte development, differentiation and activation. Nature Reviews Immunology 3(4):317-330, 2003.
- C. Sawyer, J. Sturge, D. C. Bennett, M. J. O'Hare, W. E. Allen, J. Bain, G. E. Jones, and B. Vanhaesebroeck. Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta. Cancer Research 63(7):1667-1675, 2003.
- K. Okkenhaug, A. Bilancio, G. Farjot, H. Priddle, S. Sancho, E. Peskett, W. Pearce, S. E. Meek, A. Salpekar, M. D. Waterfield, A. J. Smith, and B. Vanhaesebroeck. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297(5583):1031-1034, 2002.
- B. Vanhaesebroeck, S.J. Leevers, G. Panayatou, and M. D. Waterfield. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends in Biochemical Sciences 22(7):267-72, 1997.
- F.B. Furnari, H. Lin, H.S. Huang, and W.K. Cavenee. Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain. Proc Natl Acad Sci U S A. 94(23):12479-84, 1997
- P. Rodriguez-Viciana, P. H. Warne, R. Dhand, B. Vanhaesebroeck, I. Gout, M. J. Fry, M. D. Waterfield, and J. Downward. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370(6490):527-532, 1994.