Staff Profile:Dr Mike Fry

Name::
Position / Job Title:
Associate Professor in Biomedical Sciences
Responsibilities:
Director of Teaching and Learning
Areas of Interest:

Our recent research can be divided into three related signalling topics:

  1. The analysis of phosphoinositide (PI) 3-kinases (and in particular the class II PI 3-kinase enzymes) in signalling processes in normal and diseased cells and tissue.
  2. The use of proteomics to study protein kinase signalling.
  3. The characterization of glycogen synthase kinase 3 and its role in the Wnt signalling pathway and in platelet signalling.

Phosphoinositide (PI) 3-kinases

I have worked on the PI 3-kinase family of lipid kinases since they were first identified in the mid-1980s as a novel activity associated with activated growth factor receptors and oncogene products. PI 3-kinase activity is now linked to diverse cellular processes including cell growth and proliferation, cell differentiation, cell survival, cell motility, the regulation of gene expression and intracellular protein trafficking. They are also linked to a number of disease states including inflammation, diabetes, heart disease and atherosclerosis and cancer. This makes them potentially interesting therapeutic targets. In the last few years our focus has been on identifying and characterizing the full complement of PI 3-kinase-related enzymes in normal and malignant breast tissue. We identified a total of eight distinct mammalian PI 3-kinases and went on to cDNA clone of two novel PI 3-kinase isoforms called PI3K-C2beta/HsC2-PI3K and PI3K-C2gamma respectively. These enzymes belong to the Class II PI 3-kinase subfamily and little is known about their function. We have found that they are activated by growth factor receptors and we are currently investigating their contribution to receptor stimulated signalling pathways and to the diseased state using live-cell confocal microscopy, RNA interference (RNAi) and proteomic approaches. A recent collaboration with scientists at UCL has led to us identifying the PI3K-C2beta enzyme as playing an important role in cell migration that may result in it being important in the metastasis of cancer cells. With the increased accessibility of large-scale technologies such as RNAi and proteomics we are currently looking into more global approaches to the analysis of PI 3-kinase signalling in cells.

Proteomic analysis of protein kinases

Current predictions suggest that there are 518 protein kinases in the human genome. These enzymes play critical roles in the regulation of many cellular processes and are often implicated in various diseases such as cancer and diabetes. Selective inhibitors have been widely used to discover the cellular signalling pathways in which particular kinases function, but also more recently also as potential therapeutic agents (e.g., Gleevac). Several recent proteomic studies using immobilised kinase inhibitors as affinity reagents have shown that the spectrum of kinases that so called specific or selective inhibitors bind is wider that was initially thought. They have also highlighted other kinases that may be important therapeutic targets for certain cancers and have suggested other interpretations as to which kinase may control certain cellular processes. We are currently using this immobilised inhibitor approach (in collaboration with the Reading Biocentre) to probe various aspects of cell signalling and plan in future to develop the approach to investigate wider issues such as which kinases are expressed in which cell types, and to study the activation/post translation modification state of kinases and the complexes they form with other signalling proteins.

Wnt signaling

The Wnt signalling pathway is important during many developmental processes and also in diseases, e.g., cancer. The pathway was originally defined by epigenetic studies in Drosophila and proved to be technically difficult to study at a biochemical level. We were the first group to show that a Wnt ligand could regulate glycogen synthase kinase-3 (GSK-3) activity in a mammalian cell context. Our current studies on this pathway are aimed at looking at the signalling elements involved in early steps of the signalling pathway between the Wnt receptor and intracellular signalling components such as the adaptor molecule, Dishevelled, (Dvl), and GSK-3. In particular our efforts are focused on the role of the lipid second messengers which are generated rapidly upon Wnt binding to receptor, analysing the mechanism of their generation and the downstream signalling components to which they couple.

Research groups / Centres:
Publications:
  1. Pendaries C, Tronchere H, Arbibe L, Mounier J, Gozani O, Cantley L, Fry MJ, Gaits-Iacovoni F, Sansonetti PJ, Payrastre B. PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection. EMBO J. 2006 Mar 8;25(5):1024-34. Epub 2006 Feb 16. PMID: 16482216 [PubMed - indexed for MEDLINE]
  2. Maffucci T, Cooke FT, Foster FM, Traer CJ, Fry MJ, Falasca M. Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. J Cell Biol. 2005 Jun 6; 169(5):789-99. Epub 2005 May 31. PMID: 15928202 [PubMed - indexed for MEDLINE]
  3. Barry FA, Graham GJ, Fry MJ, Gibbins JM. Regulation of glycogen synthase kinase 3 in human platelets: a possible role in platelet function? FEBS Lett. 2003 Oct 9;553(1-2):173-8. PMID: 14550568 [PubMed - indexed for MEDLINE]
  4. Foster FM, Traer CJ, Abraham SM, Fry MJ. The phosphoinositide (PI) 3-kinase family. J Cell Sci. 2003 Aug 1;116(Pt 15):3037-40. No abstract available. PMID: 12829733 [PubMed - in process]
  5. Fry MJ. Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Res. 2001;3(5):304-12. Epub 2001 Jun 28. Review. PMID: 11597319 [PubMed - indexed for MEDLINE]
  6. Lu Y, Condie A, Bennett JD, Fry MJ, Yuille MR, Shipley J. Disruption of the ATM gene in breast cancer. Cancer Genet Cytogenet. 2001 Apr 15;126(2):97-101. PMID: 11376801 [PubMed - indexed for MEDLINE]
  7. Kamalati T, Jolin HE, Fry MJ, Crompton MR. Expression of the BRK tyrosine kinase in mammary epithelial cells enhances the coupling of EGF signalling to PI 3-kinase and Akt, via erbB3 phosphorylation. Oncogene. 2000 Nov 16;19(48):5471-6. PMID: 11114724 [PubMed - indexed for MEDLINE]
  8. Smalley MJ, Sara E, Paterson H, Naylor S, Cook D, Jayatilake H, Fryer LG, Hutchinson L, Fry MJ, Dale TC. Interaction of axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. EMBO J. 1999 May 17;18(10):2823-35. PMID: 10329628 [PubMed - indexed for MEDLINE]
  9. Rozycka M, Lu YJ, Brown RA, Lau MR, Shipley JM, Fry MJ. cDNA cloning of a third human C2-domain-containing class II phosphoinositide 3-kinase, PI3K-C2gamma, and chromosomal assignment of this gene (PIK3C2G) to 12p12. Genomics. 1998 Dec 15;54(3):569-74. PMID: 9878262 [PubMed - indexed for MEDLINE]
  10. Ho LK, Liu D, Rozycka M, Brown RA, Fry MJ. Identification of four novel human phosphoinositide 3-kinases defines a multi-isoform subfamily. Biochem Biophys Res Commun. 1997 Jun 9;235(1):130-7. PMID: 9196049 [PubMed - indexed for MEDLINE]
  11. Brown RA, Ho LK, Weber-Hall SJ, Shipley JM, Fry MJ. Identification and cDNA cloning of a novel mammalian C2 domain-containing phosphoinositide 3-kinase, HsC2-PI3K. Biochem Biophys Res Commun. 1997 Apr 17;233(2):537-44. PMID: 9144573 [PubMed - indexed for MEDLINE]
  12. Cook D, Fry MJ, Hughes K, Sumathipala R, Woodgett JR, Dale TC. Wingless inactivates glycogen synthase kinase-3 via an intracellular signalling pathway which involves a protein kinase C. EMBO J. 1996 Sep 2;15(17):4526-36. PMID: 8887544 [PubMed - indexed for MEDLINE]
  13. Woscholski R, Dhand R, Fry MJ, Waterfield MD, Parker PJ. Biochemical characterization of the free catalytic p110 alpha and the complexed heterodimeric p110 alpha.p85 alpha forms of the mammalian phosphatidylinositol 3-kinase. J Biol Chem. 1994 Oct 7;269(40):25067-72. PMID: 7929193 [PubMed - indexed for MEDLINE]
  14. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug 18;370(6490):527-32. PMID: 8052307 [PubMed - indexed for MEDLINE]
  15. Fry MJ. Structure, regulation and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1994 Jul 18;1226(3):237-68. Review. No abstract available. PMID: 8054357 [PubMed - indexed for MEDLINE]
  16. Dhand R, Hiles I, Panayotou G, Roche S, Fry MJ, Gout I, Totty NF, Truong O, Vicendo P, Yonezawa K, et al. PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J. 1994 Feb 1;13(3):522-33. PMID: 8313897 [PubMed - indexed for MEDLINE]
  17. Dhand R, Hara K, Hiles I, Bax B, Gout I, Panayotou G, Fry MJ, Yonezawa K, Kasuga M, Waterfield MD. PI 3-kinase: structural and functional analysis of intersubunit interactions. EMBO J. 1994 Feb 1;13(3):511-21. PMID: 8313896 [PubMed - indexed for MEDLINE]
  18. Fry MJ, Panayotou G, Booker GW, Waterfield MD. New insights into protein-tyrosine kinase receptor signaling complexes. Protein Sci. 1993 Nov;2(11):1785-97. Review. No abstract available. PMID: 8268793 [PubMed - indexed for MEDLINE]
  19. Gout I, Dhand R, Hiles ID, Fry MJ, Panayotou G, Das P, Truong O, Totty NF, Hsuan J, Booker GW, et al. The GTPase dynamin binds to and is activated by a subset of SH3 domains. Cell. 1993 Oct 8;75(1):25-36. PMID: 8402898 [PubMed - indexed for MEDLINE]
  20. Fry MJ, Waterfield MD. Structure and function of phosphatidylinositol 3-kinase: a potential second messenger system involved in growth control. Philos Trans R Soc Lond B Biol Sci. 1993 Jun 29;340(1293):337-44. Review. PMID: 8103937 [PubMed - indexed for MEDLINE]
  21. Panayotou G, Gish G, End P, Truong O, Gout I, Dhand R, Fry MJ, Hiles I, Pawson T, Waterfield MD. Interactions between SH2 domains and tyrosine-phosphorylated platelet-derived growth factor beta-receptor sequences: analysis of kinetic parameters by a novel biosensor-based approach. Mol Cell Biol. 1993 Jun;13(6):3567-76. PMID: 8388538 [PubMed - indexed for MEDLINE]
  22. End P, Gout I, Fry MJ, Panayotou G, Dhand R, Yonezawa K, Kasuga M, Waterfield MD. A biosensor approach to probe the structure and function of the p85 alpha subunit of the phosphatidylinositol 3-kinase complex. J Biol Chem. 1993 May 15;268(14):10066-75. PMID: 7683666 [PubMed - indexed for MEDLINE]
  23. Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science. 1993 Apr 2;260(5104):88-91.
  24. Ruiz-Larrea F, Vicendo P, Yaish P, End P, Panayotou G, Fry MJ, Morgan SJ, Thompson A, Parker PJ, Waterfield MD. Characterization of the bovine brain cytosolic phosphatidylinositol 3-kinase complex. Biochem J. 1993 Mar 1;290 ( Pt 2):609-16.
  25. Gout I, Dhand R, Panayotou G, Fry MJ, Hiles I, Otsu M, Waterfield MD. Expression and characterization of the p85 subunit of the phosphatidylinositol 3-kinase complex and a related p85 beta protein by using the baculovirus expression system. Biochem J. 1992 Dec 1;288 ( Pt 2):395-405.
  26. Panayotou G, Bax B, Gout I, Federwisch M, Wroblowski B, Dhand R, Fry MJ, Blundell TL, Wollmer A, Waterfield MD. Interaction of the p85 subunit of PI 3-kinase and its N-terminal SH2 domain with a PDGF receptor phosphorylation site: structural features and analysis of conformational changes. EMBO J. 1992 Dec;11(12):4261-72.
  27. Fry MJ, Panayotou G, Dhand R, Ruiz-Larrea F, Gout I, Nguyen O, Courtneidge SA, Waterfield MD. Purification and characterization of a phosphatidylinositol 3-kinase complex from bovine brain by using phosphopeptide affinity columns. Biochem J. 1992 Dec 1;288 ( Pt 2):383-93.
  28. Ward SG, Reif K, Ley S, Fry MJ, Waterfield MD, Cantrell DA. Regulation of phosphoinositide kinases in T cells. Evidence that phosphatidylinositol 3-kinase is not a substrate for T cell antigen receptor-regulated tyrosine kinases. J Biol Chem. 1992 Nov 25;267(33):23862-9.
  29. Bardelli A, Maina F, Gout I, Fry MJ, Waterfield MD, Comoglio PM, Ponzetto C. Autophosphorylation promotes complex formation of recombinant hepatocyte growth factor receptor with cytoplasmic effectors containing SH2 domains. Oncogene. 1992 Oct;7(10):1973-8.
  30. Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, Panayotou G, Ruiz-Larrea F, Thompson A, Totty NF, et al. Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell. 1992 Aug 7;70(3):419-29.
  31. Zhang J, Fry MJ, Waterfield MD, Jaken S, Liao L, Fox JE, Rittenhouse SE. Activated phosphoinositide 3-kinase associates with membrane skeleton in thrombin-exposed platelets. J Biol Chem. 1992 Mar 5;267(7):4686-92.
  32. Panayotou G, Fry MJ, Waterfield MD. Multi-enzyme complexes associated with receptors during signal transduction. C R Acad Sci III. 1992;314(9 Suppl):11-20. Review. English, French. No abstract available.
  33. Wetzker R, Klinger R, Hsuan J, Fry MJ, Kauffmann-Zeh A, Muller E, Frunder H, Waterfield M. Purification and characterization of phosphatidylinositol 4-kinase from human erythrocyte membranes. Eur J Biochem. 1991 Aug 15;200(1):179-85.
  34. Otsu M, Hiles I, Gout I, Fry MJ, Ruiz-Larrea F, Panayotou G, Thompson A, Dhand R, Hsuan J, Totty N, et al. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase. Cell. 1991 Apr 5;65(1):91-104.
  35. Bell JC, Mahadevan L, Colledge WH, Fry MJ, Frackelton AR, Sargent MG, Foulkes JG. Mechanisms of transformation by protein-tyrosine kinases. Adv Exp Med Biol. 1988;231:475-80. No abstract available.
  36. Fry MJ, Gebhardt A, Parker PJ, Foulkes JG. Phosphatidylinositol turnover and transformation of cells by Abelson murine leukaemia virus. EMBO J. 1985 Dec 1;4(12):3173-8.

Contact Details

Email:
m.j.fry@reading.ac.uk
Telephone:
+44 (0) 118 378 7028

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