Shehab Ismail - Spatial Segregation of Signalling

Introduction

Ismail Shehab

At equilibrium, entropy (disorder) tends to increase, since disorder is more probable than order. Life exists away from equilibrium and our cells have developed mechanisms to counteract disorder. Spatial and temporal segregation/organisation of proteins of opposite functions is crucial for controlling cell signalling output, for example separating phosphatases and kinases or the small GTPases regulators, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Our group is interested in studying self-organised cellular compartments that participate in cell signalling without being separated from the rest of the cell by membranes. In particular, we are interested in the cilia and immunological synapses.

The primary cilium is a microtubule-based sensory organelle that is present on almost all cell types in the body. The assembly of the cilium is tightly synchronised with the cell cycle and coordinates several signalling pathways such as the Wnt and Hedgehog pathways, both of which are therapeutic targets for cancer. Concentrating signalling proteins and receptors inside the cilium is key to its function. Nevertheless, the cilium, unlike other organelles, is not separated from the cell body by a membrane barrier, and the molecular mechanism by which ciliary proteins are concentrated in the cilia is elusive.

Although lymphocytes lack cilia, they form a structure called the immunological synapse, which shows striking similarities to the cilium (Dustin, 2014; Stinchcombe & Griffiths, 2014). Lymphocytes use the immunological synapse to communicate with other cells, including tumour cells, and regulate the immune response. Upon identification of a match between a T-cell receptor and an antigen-MHC complex from the target cell (such as a tumour cell), several signalling molecules concentrate at the interface between both cells. This leads to the rearrangement of membrane proteins and the cytoskeleton, resulting in the formation of the immunological synapse.

In our laboratory we combine structural biology, biochemistry and cell biology to investigate the atomic basis of cellular mechanisms that maintain the distinct composition of the cilia and immunological synapses. We take advantage of the similarities between cilia and immunological synapses and cross-test information that we generate from both cellular structures. We aim to develop cancer therapeutics by manipulating the spatial organisation of these protein networks and hence the output of their signalling compartments.

Lab Report

icon Ismail Lab Report

Key Recent Publications

Alkanderi S, Molinari E, Shaheen R, Elmaghloob Y, Stephen LA, Sammut V, Ramsbottom SA, Srivastava S, Cairns G, Edwards N, Rice SJ, Ewida N, Alhashem A, White K, Miles CG, Steel DH, Alkuraya FS, Ismail S, Sayer JA. ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition. Am J Hum Genet 2018;103(4):612-20. doi: 10.1016/j.ajhg.2018.08.015

Stephen LA, ElMaghloob Y, McIlwraith MJ, Yelland T, Castro Sanchez P, Roda-Navarro P, Ismail S. The Ciliary Machinery Is Repurposed for T Cell Immune Synapse Trafficking of LCK. Dev Cell 2018. doi: 10.1016/j.devcel.2018.08.012

Ismail SA. A GDI/GDF like system for sorting and shuttling ciliary proteins. Small GTPases, 2016 Aug, Epub ahead of print

Fansa EK, Kösling SK, Zent E, Wittinghofer A, Ismail S. PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nat Commun 7, 11366, 2016. doi: 10.1038/ncomms11366

Zimmermann G*, Papke B*, Ismail S*, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PIH, Waldmann H. Small Molecule Inhibition of the Kras-PDEδ Interaction Impairs Oncogenic Kras Signaling. Nature 497:638-42, 2013 *authors contributed equally

Wätzlich D, Vetter I, Gotthardt K, Miertzschke M, Chen Y-X, Wittinghofer A, Ismail S. The interplay between RPGR, PDEδ and Arl2/3 regulates the ciliary targeting of farnesylated cargo. EMBO Rep. 14:465-72, 2013

Ismail SA, Chen Y-X, Miertzschke M, Vetter I, Carolin K, Wittinghofer A. Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. EMBO J. 31:4085-94, 2012

Ismail SA, Chen Y-X, Rusinova A, Chandra A, Bierbaum M, Gremer L, Triola G, Waldmann H, Bastiaens PIH, Wittinghofer A. Arl2 and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo. Nat Chem Biol. 7:942-9, 2011

Ismail SA, Vetter IR, Sot B, Witinghofer A. The structure of an Arf-ArfGAP complex reveals a Ca2+ regulatory mechanism. Cell 141:812-21, 2010

Biography

Education and qualifications

2005: PhD, University of Tennessee/St Jude Children's Research Hospital, USA
2000: BSc, Pharmacy, Cairo University, Egypt

Appointments

2014-present: Junior Group Leader, CRUK Beatson Institute
2007-2014: Postdoctoral Fellow, Department of Structural Biology, Max-Planck-Institute, Dortmund, Germany, with Prof Alfred Wittinghofer
2006-2007: Lecturer, The German University in Cairo, Egypt
2005-2006: Postdoctoral Fellow, Structural Genomics Consortium, University of Toronto, Canada, with Dr Hee Won Park

Honours and awards

Alexander Von Humboldt Fellowship, 2007-2009

Recent Publications

2018

Alkanderi S, Molinari E, Shaheen R, Elmaghloob Y, Stephen LA, Sammut V, Ramsbottom SA, Srivastava S, Cairns G, Edwards N, Rice SJ, Ewida N, Alhashem A, White K, Miles CG, Steel DH, Alkuraya FS, Ismail S, Sayer JA. ARL3 Mutations Cause Joubert Syndrome by Disrupting Ciliary Protein Composition. Am J Hum Genet 2018;103(4):612-20. doi: 10.1016/j.ajhg.2018.08.015

Fort L, Batista JM, Thomason PA, Spence HJ, Whitelaw JA, Tweedy L, Greaves J, Martin KJ, Anderson KI, Brown P, Lilla S, Neilson MP, Tafelmeyer P, Zanivan S, Ismail S, Bryant DM, Tomkinson NCO, Chamberlain LH, Mastick GS, Insall RH, Machesky LM. Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nat Cell Biol. 2018 Oct; 20(10): 1159-71. doi: 10.1038/s41556-018-0198-9

Stephen LA, ElMaghloob Y, McIlwraith MJ, Yelland T, Castro Sanchez P, Roda-Navarro P, Ismail S. The Ciliary Machinery Is Repurposed for T Cell Immune Synapse Trafficking of LCK. Dev Cell 2018. doi: 10.1016/j.devcel.2018.08.012

2017

Gray CH, Konczal J, Mezna M, Ismail S, Bower J, Drysdale M. A fully automated procedure for the parallel, multidimensional purification and nucleotide loading of the human GTPases KRas, Rac1 and RalB. Protein Expr Purif 2017; 132: 75-84

Hernandez-Fernaud JR, Ruengeler E, Casazza A, Neilson LJ, Pulleine E, Santi A, Ismail S, Lilla S, Dhayade S, MacPherson IR, McNeish I, Ennis D, Ali H, Kugeratski FG, Al Khamici H, van den Biggelaar M, van den Berghe PV, Cloix C, McDonald L, Millan D et al. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. Nat Commun 2017; 8: 14206

Martín-Gago P, Fansa EK, Klein CH, Murarka S, Janning P, Schürmann M, Metz M, Ismail S, Schultz-Fademrecht C, Baumann M, Bastiaens PIH, Wittinghofer A, Waldmann H. A PDE6delta-KRas Inhibitor Chemotype with up to Seven H-Bonds and Picomolar Affinity that Prevents Efficient Inhibitor Release by Arl2. Angew Chem 2017; 129: 2463

Murarka S, Martin-Gago P, Schultz-Fademrecht C, Al Saabi A, Baumann M, Fansa EK, Ismail S, Nussbaumer P, Wittinghofer A, Waldmann H. Development of Pyridazinone Chemotypes Targeting the PDEdelta Prenyl Binding Site. Chemistry 2017; 23: 6083-93

Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Roman-Fernandez A, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J 2017; 36: 2373-89

Ismail S. A GDI/GDF-like system for sorting and shuttling ciliary proteins. Small GTPases 2017; 8: 208-11

Stephen L, Elmaghloob Y, Ismail S. Maintaining protein composition in cilia. Biol Chem 2017; 399: 1-11

2016

Fansa EK, Kösling SK, Zent E, Wittinghofer A, Ismail S. PDE6δ-mediated sorting of INPP5E into the cilium is determined by cargo-carrier affinity. Nat Commun 7, 11366, 2016

Murarka S, Martín-Gago P, Schultz-Fademrecht C, Al Saabi A, Baumann M, Fansa E, Ismail S, Nussbaumer P, Wittinghofer A, Waldmann H. Development of Pyridazinone Chemotypes Targeting the PDEδ Prenyl Binding Site. Chemistry, 2016 Nov 3, doi: 10.1002/chem.201603222

Papke B, Murarka S, Vogel HA, Martín-Gago P, Kovacevic M, Truxius DC, Fansa EK, Ismail S, Zimmermann G, Heinelt K, Schultz-Fademrecht C, Al Saabi A, Baumann M, Nussbaumer P, Wittinghofer A, Waldmann H, Bastiaens PI. Identification of pyrazolopyridazinones as PDEδ inhibitors. Nat Commun 7, 11360, 2016

Ismail SA. A GDI/GDF like system for sorting and shuttling ciliary proteins. Small GTPases, 2016 Aug 3: 1-4, 2016

Stephen LA, Ismail S. Shuttling and sorting lipid-modified cargo into the cilia. Biochem Soc Trans 44, 1273-80, 2016

2015

Fansa EK, O'Reilly N, Ismail S, Wittinghofer A. The N- and C-terminal ends of RPGR can bind to PDE6d. EMBO Reports 16, 1583-5, 2015

Kapoor S, Fansa EK, Möbitz S, Ismail SA, Winter R, Wittinghofer A, Weise K. Effect of the N-Terminal Helix and Nucleotide Loading on the Membrane and Effector Binding of Arl2/3. Biophys J 109: 1619-29, 2015

2014

Bravo-Rodriguez K, Ismail-Ali AF, Klopries S, Kushnir S, Ismail S, Fansa EK, Wittinghofer A, Schulz F, Sanchez-Garcia E. Predicted Incorporation of Non-native Substrates by a Polyketide Synthase Yields Bioactive Natural Product Derivatives. ChemBioChem 15: 1991-7, 2014

Suladze S, Ismail S, Winter R. Thermodynamic, dynamic and solvational properties of PDEdelta binding to farnesylated cystein: a model study for uncovering the molecular mechanism of PDEdelta interaction with prenylated proteins. J Phys Chem B 118: 966-75, 2014

Zimmermann G, Schultz-Fademrecht C, Kuchler P, Murarka S, Ismail S, Triola G, Nussbaumer P, Wittinghofer A, Waldmann H. Structure Guided Design and Kinetic Analysis of Highly Potent Benzimidazole Inhibitors Targeting the PDEdelta Prenyl Binding Site. J Med Chem 57: 5435-48, 2014

Lab Members

ismail group

Post-docs

Louise Stephen
Tamas Yelland

Senior Scientific Officer

Michael McIlwraith

PhD Student

Yasmin El Maghloob

Research

At the bench 3 160

Read more about the Research Groups working at the Beatson Institute.

More

Seminars

Running a gel 154

Find out more about our seminars including our Distinguished Seminar Programme.

More