Member Listing

Name

Phill Hawkins

Affiliation

The Babraham Institute

Title

Dr

Role

Principal Investigator

Research Summary

The programmes of work in the laboratory are currently aimed at understanding the molecular mechanisms and physiological significance of intracellular signalling networks which involve a family of enzymes called phosphoinositide 3OH-kinases (PI3Ks).

PI3Ks are now accepted to be critical regulators of numerous important and complex cell responses, including cell growth, division, survival and movement. PI3Ks catalyse the formation of one or more critical phospholipid messenger molecules, which signal information by binding to specific domains in target proteins. Currently the best understood pathway involves the activation of Class I PI3Ks by cell surface receptors.

In recent years, the laboratory has increasingly focused on the role of PI3Ks in the signalling mechanisms which allow receptors on neutrophils (white blood cells) to control various aspects of neutrophil function. Neutrophils are key players in the front line of our immune system, responsible primarily for the recognition and destruction of bacterial and fungal pathogens. However, they are also involved in the amplification cascades that underlie various inflammatory pathologies, e.g. Acute Respiratory Distress Syndrome (ARDS) and rheumatoid arthritis.

Expertise

Biochemistry and Molecular Biology, Cell Biology, Immunology

Selected Publications

Deladeriere A, Gambardella L, Pan D, Anderson KE, Hawkins PT, Stephens LR. The regulatory subunits of PI3Kγ control distinct neutrophil responses. Science signaling, 8, 1937-9145, ra8, 2015. PMID: 25605974

Schiebler M, Brown K, Hegyi K, Newton SM, Renna M, Hepburn L, Klapholz C, Coulter S, Obregón-Henao A, Henao Tamayo M, Basaraba R, Kampmann B, Henry KM, Burgon J, Renshaw SA, Fleming A, Kay RR, Anderson KE, Hawkins PT, Ordway DJ, Rubinsztein DC, Floto RA. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO molecular medicine, 7, 1757-4684, 127-39, 2014. PMID: 25535254

Clark J,Kay RR,Kielkowska A,Niewczas I,Fets L,Oxley D,Stephens LR,Hawkins PT. Dictyostelium uses ether-linked inositol phospholipids for intracellular signalling. The EMBO journal, , 1460-2075, , 2014. PMID: 25180230

Jones DR, Keune WJ, Anderson KE, Stephens LR, Hawkins PT, Divecha N. The hexosamine biosynthesis pathway and O-GlcNAcylation maintain insulin-stimulated PI3K-PKB phosphorylation and tumour cell growth after short-term glucose deprivation. The FEBS journal, 281, 1742-4658, 3591-608, 2014. PMID: 24938479

Győri D, Csete D, Benkő S, Kulkarni S, Mandl P, Dobó-Nagy C, Vanhaesebroeck B, Stephens L, Hawkins PT, Mócsai A. The phosphoinositide 3-kinase isoform PI3Kβ regulates osteoclast-mediated bone resorption in humans and mice. Arthritis & rheumatology (Hoboken, N.J.), 66, 2326-5205, 2210-21, 2014. PMID: 24719382

G Damoulakis, L Gambardella, KL Rossman, CD Lawson, KE Anderson, Y Fukui, HC Welch, CJ Der, LR Stephens, PT Hawkins. P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils. Journal of cell science, 127, Pt 11, 2589-600, 2014. PMID: 24659802

Hodakoski C, Hopkins BD, Barrows D, Mense SM, Keniry M, Anderson KE, Kern PA, Hawkins PT, Stephens LR, Parsons R. Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 111, 1091-6490, 155-60, 2014. PMID: 24367090

I Angulo, O Vadas, F Garçon, E Banham-Hall, V Plagnol, TR Leahy, H Baxendale, T Coulter, J Curtis, C Wu, K Blake-Palmer, O Perisic, D Smyth, M Maes, C Fiddler, J Juss, D Cilliers, G Markelj, A Chandra, G Farmer, A Kielkowska, J Clark, S Kracker, M Debré, C Picard, I Pellier, N Jabado, JA Morris, G Barcenas-Morales, A Fischer, L Stephens, P Hawkins, JC Barrett, M Abinun, M Clatworthy, A Durandy, R Doffinger, E Chilvers, AJ Cant, D Kumararatne, K Okkenhaug, RL Williams, A Condliffe, S Nejentsev. Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage. Science (New York, N.Y.), 2013. PMID: 24136356

Juvin V, Malek M, Anderson KE, Dion C, Chessa T, Lecureuil C, Ferguson GJ, Cosulich S, Hawkins PT, Stephens LR. Signaling via class IA Phosphoinositide 3-kinases (PI3K) in human, breast-derived cell lines. PloS one, 8, 1932-6203, e75045, 2013. PMID: 24124465

L Stephens, P Hawkins. More paths to PI3Kγ. PLoS biology, 11, 6, e1001594, 2013. PMID: 23853549

O Hoeller, P Bolourani, J Clark, LR Stephens, PT Hawkins, OD Weiner, G Weeks, RR Kay. Two distinct functions for PI3-kinases in macropinocytosis. Journal of cell science, 126, Pt 18, 4296-307, 2013. PMID: 23843627

KE Anderson, A Kielkowska, TN Durrant, V Juvin, J Clark, LR Stephens, PT Hawkins. Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse. PloS one, 8, 3, e58425, 2013. PMID: 23472195

KB Boyle, LR Stephens, PT Hawkins. Activation of the neutrophil NADPH oxidase by Aspergillus fumigatus. Annals of the New York Academy of Sciences, 1273, , 68-73, 2012. PMID: 23230839

L Gambardella, KE Anderson, Z Jakus, M Kovács, S Voigt, PT Hawkins, L Stephens, A Mócsai, S Vermeren. Phosphoinositide 3-OH kinase regulates integrin-dependent processes in neutrophils by signaling through its effector ARAP3. Journal of immunology (Baltimore, Md. : 1950), 190, 1, 381-91, 2013. PMID: 23180820

JK Juss, RP Hayhoe, CE Owen, I Bruce, SR Walmsley, AS Cowburn, S Kulkarni, KB Boyle, L Stephens, PT Hawkins, ER Chilvers, AM Condliffe. Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. PloS one, 7, 9, e45933, 2012. PMID: 23029326

B Vanhaesebroeck, L Stephens, P Hawkins. PI3K signalling: the path to discovery and understanding. Nature reviews. Molecular cell biology, 13, 3, 195-203, 2012. PMID: 22358332

MA Vinolo, GJ Ferguson, S Kulkarni, G Damoulakis, K Anderson, M Bohlooly-Y, L Stephens, PT Hawkins, R Curi. SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor. PloS one, 6, 6, e21205, 2011. PMID: 21698257

L Gambardella, KE Anderson, C Nussbaum, A Segonds-Pichon, T Margarido, L Norton, T Ludwig, M Sperandio, PT Hawkins, L Stephens, S Vermeren. The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils. Blood, 118, 4, 1087-98, 2011. PMID: 21490342

S Kulkarni, C Sitaru, Z Jakus, KE Anderson, G Damoulakis, K Davidson, M Hirose, J Juss, D Oxley, TA Chessa, F Ramadani, H Guillou, A Segonds-Pichon, A Fritsch, GE Jarvis, K Okkenhaug, R Ludwig, D Zillikens, A Mocsai, B Vanhaesebroeck, LR Stephens, PT Hawkins. PI3Kβ plays a critical role in neutrophil activation by immune complexes. Science signaling, 4, 168, ra23, 2011. PMID: 21487106

X Zhang, O Vadas, O Perisic, KE Anderson, J Clark, PT Hawkins, LR Stephens, RL Williams. Structure of lipid kinase p110β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism. Molecular cell, 41, 5, 567-78, 2011. PMID: 21362552

J Clark, KE Anderson, V Juvin, TS Smith, F Karpe, MJ Wakelam, LR Stephens, PT Hawkins. Quantification of PtdInsP3 molecular species in cells and tissues by mass spectrometry. Nature methods, 8, 3, 267-72, 2011. PMID: 21278744

KB Boyle, D Gyori, A Sindrilaru, K Scharffetter-Kochanek, PR Taylor, A Mócsai, LR Stephens, PT Hawkins. Class IA phosphoinositide 3-kinase β and δ regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae. Journal of immunology (Baltimore, Md. : 1950), 186, 5, 2978-89, 2011. PMID: 21257963

L Stephens, P Hawkins. Signalling via class IA PI3Ks. Advances in enzyme regulation, 51, 1, 27-36, 2011. PMID: 21035483

TA Chessa, KE Anderson, Y Hu, Q Xu, O Rausch, LR Stephens, PT Hawkins. Phosphorylation of threonine 154 in p40phox is an important physiological signal for activation of the neutrophil NADPH oxidase. Blood, 116, 26, 6027-36, 2010. PMID: 20861461

KE Anderson, TA Chessa, K Davidson, RB Henderson, S Walker, T Tolmachova, K Grys, O Rausch, MC Seabra, VL Tybulewicz, LR Stephens, PT Hawkins. PtdIns3P and Rac direct the assembly of the NADPH oxidase on a novel, pre-phagosomal compartment during FcR-mediated phagocytosis in primary mouse neutrophils. Blood, 116, 23, 4978-89, 2010. PMID: 20813901