Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival

Extent: 14 p.The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.Daniel Thomas, Jason A. Powell, Benjamin D. Green, Emma F. Barry, Yuefang Ma, Joanna Woodcock, Stephen Fitter, Andrew C.W. Zannettino, Stuart M. Pitson, Timothy P. Hughes, Angel F. Lopez, Peter R. Shepherd, Andrew H. Wei, Paul G. Ekert and Mark A. Guthridg

Protein Phosphatase Magnesium Dependent 1A (PPM1A) Plays a Role in the Differentiation and Survival Processes of Nerve Cells

The serine/threonine phosphatase type 2C (PPM1A) has a broad range of substrates, and its role in regulating stress response is well established. We have investigated the involvement of PPM1A in the survival and differentiation processes of PC6-3 cells, a subclone of the PC12 cell line. This cell line can differentiate into neuron like cells upon exposure to nerve growth factor (NGF). Overexpression of PPM1A in naive PC6-3 cells caused cell cycle arrest at the G2/M phase followed by apoptosis. Interestingly, PPM1A overexpression did not affect fully differentiated cells. Using PPM1A overexpressing cells and PPM1A knockdown cells, we show that this phosphatase affects NGF signaling in PC6-3 cells and is engaged in neurite outgrowth. In addition, the ablation of PPM1A interferes with NGF-induced growth arrest during differentiation of PC6-3 cells

Crop Updates 2000 - Pulses

This session covers fifty nine papers from different authors: 1.1999 PULSE INDUSTRY HIGHLIGHTS 2. CONTRIBUTORS 3. BACKGROUND 4. SUMMARY OF PREVIOUS RESULTS 5. 1999 REGIONAL ROUNDUP 6. Northern Agricultural Region, W. O’Neill, AGWEST 7. Central Agricultural Region J. Russell and R.J. French AGWEST 8. Great Southern and Lakes N. Brandon, C. Gaskin and N. Runciman, AGWEST 9. Esperance Mallee M. Seymour, AGWEST PULSE PRODUCTION AGRONOMY AND GENETIC IMPROVEMENT 10. Faba Bean 11. Desi chickpea Traits associated with drought resistance in chickpea, J. Berger, N.C. Turner, CLIMA and CSIRO Plant Industry, R.J. French, AGWEST, R. Carpenter, C. Ludwig and R. Kenney, CSIRO Plant Industry 12. Genotype x environment analysis of chickpea adaptation, J. Berger and N. Turner, CLIMA and CSIRO Plant Industry, and K.H.M. Siddique, AGWEST 13. Carbon fixation by chickpea pods under terminal drought, Q. Ma, CLIMA, M.H. Behboudian, Massey University, New Zealand, N.C. Turner and J.A. Palta, CLIMA, and CSIRO Plant Industry 14. Influence of terminal drought on growth and seed quality, M.H. Behboudian, Massey University, New Zealand, Q. Ma, CLIMA, N.C. Turner and J.A. Palta, CSIRO Plant Industry 15. Resistance to chilling at flowering and to budworm, H. Clarke, CLIMA Chickpea nodulation survey, J. Stott and J. Howieson, Centre for Rhizobium Studies, Murdoch University 16. Kabuli chickpea 17. Premium quality kabuli chickpea development in the ORIA, K.H.M. Siddique CLIMA and AGWEST, K.L. Regan, AGWEST, R. Shackles, AGWEST 18. International screening for Ascochyta blight resistance, K.H.M. Siddique CLIMA and AGWEST, C. Francis, CLIMA, K.L. Regan, AGWEST, N. Acikgoz and N. Atikyilmaz, AARI, Turkey and R.S. Malholtra, ICARDA, Syria 19. Agronomic evaluation of Ascochyta resistant kabuli germplasm in WA, K.H.M. Siddique CLIMA and AGWESTC. Francis, CLIMA, K.L. Regan and M. Baker, AGWEST 20. Field Pea 21. Lentil 22. ACIAR project J. Clements, K.H.M. Siddique CLIMA and AGWEST and C. Francis CLIMA 23. Vetch 24. Rust, M. Seymour, AGWEST 25. Narbon bean 26. Agronomy, M. Seymour, AGWEST 27. Lupinus species 28. Screening lupins for tolerance to alkaline/calcareous soils, C. Tang, CLIMA andUniversity of WAand J.D. Brand, WAITE, University of Adelaide 29. Lathyrus development, C. Hanbury and K.H.M. Siddique, CLIMA and AGWEST 30. Sheep feeding studies, C. White, CSIRO, Perth, C. Hanbury, CLIMA and K.H.M. Siddique, CLIMA and AGWEST 31. Lathyrus: a potential new ingredient in pig diets, B.P. Mullan, C.D. Hanbury and K.H.M. Siddique, AGWEST 32. Species comparison 33. Species for horticultural rotations, K.H.M. Siddique, AGWEST, R. Lancaster and I. Guthridge AGWEST 34. Marrow fat field pea shows promise in the southwest, K.H.M. Siddique, AGWEST, N. Runciman, AGWEST, and I. Pritchard, AGWEST, 35. Pulses on grey clay soils, P. Fisher, M. Braimbridge, J. Bignell, N. Brandon, R. Beermier, W. Bowden, AGWEST 36. Nutrient management of pulses 37. Summary of pulse nutrition studies in WA, M.D.A. Bolland, K.H.M. Siddique, G.P. Riethmuller, and R.F. Brennan, AGWEST 38. Pulse species response to phosphorus and zinc, S. Lawrence, Zed Rengel, University of WA, S.P. Loss, CSBP futurefarm, M.D.A. Bolland, .H.M. Siddique, W. Bowden, AGWEST 39. Gypsum 40. Antitranspirants seed priming DEMONSTRATION OF PULSES IN THE FARMING SYSTEM 41. Foliar and soil applied nutrients for field peas in the south coast mallee,M. Seymour, AGWEST, and P. Vedeniapine, Phosyn Ltd 42. Demonstration of pulse species at Kendenup, C. Kirkwood, Farmer, Katanning, R. Beermier, N. Runciman and N. Brandon, AGWEST 43. Kabuli chickpea demonstration at Gnowangerup, R. Beermier and N. Brandon, AGWEST 44. Lathyrus sativus demonstration at Mindarabin, N. Brandon and R. Beermier, AGWEST 45. New field pea varieties in the central eastern region, J. Russell, AGWEST DISEASE AND PEST MANAGEMENT 46. Ascochyta blight of chickpea 47. Botrytis grey mould (BGM) of chickpea 48. Fungal disease diagnostics, Pulse disease diagnostics, D. Wright, AGWEST Plant Laboratories 49. Viruses in pulses, Luteovirus infection in field pea and faba bean crops, and viruses in seed, L. Latham, CLIMA and AGWEST, R. Jones, AGWEST 50. Screening of pulse species for pea seed-borne mosaic virus, L. Latham, CLIMAand AGWEST, and R. Jones, AGWEST 51. CMV in chickpea: effect of seed-borne sources on virus spread and seed yield, R. Jones, AGWEST and L. Latham, CLIMA and AGWEST 52. Insect pests 53. Evaluation of transgenic field pea against the pea weevil,M.J. de Sousa Majer, School of Environmental Biology, Curtin University of Technology,, D. Hardie, and N.C. Turner, CSIRO Division of Plant Industry 54. Development of a molecular marker for pea weevil resistance in field pea, Oonagh Byrne, CLIMA, Darryl Hardie, AGWEST and Penny Smith, UWA 55. Aphid feeding damage to faba bean and lentil crops, Françoise Berlandier, AGWEST 56. Taxonomy and control of bruchids in pulses, N. Keals, CLIMA, D. Hardie and R. Emery, AGWEST, 57. ACKNOWLEDGMENTS 58. PUBLICATIONS BY PULSE PRODUCTIVITY PROJECT STAFF 59. VARIETIES PRODUCED AND COMMERCIALLY RELEASE

Science amongst the vines. Meeting on Signalling Systems

Copyright © 2008 by the European Molecular Biology OrganizationStuart M Pitson, Gregory J Goodall and Mark A Guthridg

Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch

Copyright © 2006 by the European Molecular Biology OrganizationPleiotropism is a hallmark of cytokines and growth factors; yet, the underlying mechanisms are not clearly understood. We have identified a motif in the granulocyte macrophage-colony-stimulating factor receptor composed of a tyrosine and a serine residue that functions as a binary switch for the independent regulation of multiple biological activities. Signalling occurs either through Ser585 at lower cytokine concentrations, leading to cell survival only, or through Tyr577 at higher cytokine concentrations, leading to cell survival as well as proliferation, differentiation or functional activation. The phosphorylation of Ser585 and Tyr577 is mutually exclusive and occurs via a unidirectional mechanism that involves protein kinase A and tyrosine kinases, respectively, and is deregulated in at least some leukemias. We have identified similar Tyr/Ser motifs in other cell surface receptors, suggesting that such signalling switches may play important roles in generating specificity and pleiotropy in other biological systems.Mark A Guthridge, Jason A Powell, Emma F Barry, Frank C Stomski, Barbara J McClure, Hayley Ramshaw, Fernando A Felquer, Mara Dottore, Daniel T Thomas, Bik To, C Glenn Begley and Angel F Lope