Jim Norman - Integrin Cell Biology

Introduction

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Integrins are cell adhesion receptors involved in mediating the invasive migration, growth and metastasis of cancer cells. Data from our lab and our collaborators has established that Rab-regulated integrin trafficking contributes to cancer cell migration.

Indeed, we have now obtained detailed descriptions of the molecular machinery of integrin transport and determined how this contributes to invasive migration of cancer cells through three-dimensional matrices.

Furthermore, we have identified components of the cell's machinery for processing and transporting mRNA that make key contributions to cancer cell invasion. We are currently evaluating the molecular components of these novel pathways as potential targets for anti-cancer therapy and patient screening strategies.

Lab Report

Research Highlights

  • First description of the role of Rab GTPases and cell signalling pathways that control integrin recycling – key to this work was the development of assays to measure integrin trafficking which have subsequently been widely used by others in the field (Curr Biol 11:1).
  • The first proteomic investigations of an endosomally-located receptor reveals PKD1 to be a partner for an integrin that regulates intracellular trafficking by phosphorylating a Rab effector (EMBO J 23:2531; J Cell Biol 177:515; Dev Cell 23:560).
  • The development of novel photoactivation approaches to study integrin trafficking in living cells (Dev Cell 13:496).
  • The first descriptions of the contributions made by integrin trafficking to tumour cell invasion and cell migration in 3D contexts. Key to this work was the discovery of mutant p53’s gain of function to drive invasion via Rab-coupling protein recycling (J Cell Biol 183:143; Cell 139:1327)
  • Discovery of a new pathway active in cancer cells that opposes degradation of lysosomally-targetted integrins and allows their return to the plasma membrane. CLIC3, the regulator of this pathway, provides the first clear link between adhesion receptor trafficking and the progression of cancer in humans (Dev Cell 17:131)

Key Recent Publications

Christoforides C, Rainero E, Brown KK, Norman JC* and Toker A*. PKD Controls αvβ3 Integrin Recycling and Tumor Cell Invasive Migration Through its Substrate Rabaptin-5. Dev Cell 23:560-572, 2012 *joint corresponding authors

Muller PA, Trinidad AG, Timpson P, Morton JP, Zanivan S, van den Berghe PV, Nixon C, Karim SA, Caswell PT, Noll JE, Coffill CR, Lane DP, Sansom OJ, Neilsen PM, Norman JC*, Vousden KH*. Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene 32: 1252-65, 2012 *joint corresponding authors

Dozynkiewicz MA, Jamieson NB, Macpherson I, Grindlay J, van den Berghe PV, von Thun A, Morton JP, Gourley C, Timpson P, Nixon C, McKay CJ, Carter R, Strachan D, Anderson K, Sansom OJ, Caswell PT, Norman JC. Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression. Dev Cell 17: 131-45, 2012

Rainero E, Caswell PT, Muller PA, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJ, Vousden KH, Graziani A, Norman JC. Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biology. 196: 277, 2012

von Thun A, Birtwistle M, Kalna G, Grindlay J, Strachan D, Kolch W and von Kriegsheim A, Norman JC. ERK2 drives tumour cell migration in 3D microenvironments by suppressing expression of Rab17 and Liprin-β2. J Cell Science 125: 1465, 2012

Biography

Education and qualifications

1992: PhD, University of London
1985: BSc, Biochemistry, University of Southampton

Appointments

2009-present: Senior Group Leader, CRUK Beatson Institute
2005-2009: Junior Group Leader, CRUK Beatson Institute
2000-2005: Lecturer, Dept. Biochemistry, University of Leicester
1999-2004: Wellcome Career Development Fellow, Dept. Biochemistry, University of Leicester
1996-1998: Postdoctoral Fellow, Dept. Biochemistry, University of Leicester
1994-1996: Postdoctoral Fellow, Physiological Laboratory, University of Cambridge
1992-1994: Postdoctoral Fellow, Dept. Physiology, University College London

Honours and awards

Wellcome Trust Career Development Award, 1999-2004

Recent Publications

2015

Rainero E, Howe JD, Caswell PT, Jamieson NB, Anderson K, Critchley DR, Machesky L, Norman JC. Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration. Cell Rep 2015. doi: 10.1016/j.celrep.2014.12.037. Epub 2015 Jan 15

2014

Haugsten EM, Brech A, Liestol K, Norman JC, Wesche J. Photoactivation approaches reveal a role for Rab11 in FGFR4 recycling and signalling. Traffic 15: 665-83, 2014

Macagno JP, Diaz Vera J, Yu Y, MacPherson I, Sandilands E, Palmer R, Norman JC, Frame M, Vidal M. FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells. PLoS Genet 10: e1004262, 2014

Macpherson IR, Rainero E, Mitchell LE, van den Berghe PV, Speirs C, Dozynkiewicz MA, Chaudhary S, Kalna G, Edwards J, Timpson P, Norman JC. CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer. J Cell Sci 127: 3893-901, 2014

Rainero E, Cianflone C, Porporato PE, Chianale F, Malacarne V, Bettio V, Ruffo E, Ferrara M, Benecchia F, Capello D, Paster W, Locatelli I, Bertoni A, Filigheddu N, Sinigaglia F, Norman JC, Baldanzi G, Graziani A. The Diacylglycerol Kinase alpha/Atypical PKC/beta1 Integrin Pathway in SDF-1alpha Mammary Carcinoma Invasiveness. PLoS One 9: e97144, 2014

2013

Campbell AD, Lawn S, McGarry LC, Welch HC, Ozanne BW and Norman JC. P-Rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments. PLoS ONE 8(1): e53982, 2013

Muller PA, Trinidad AG, Timpson P, Morton JP, Zanivan S, van den Berghe PV, Nixon C, Karim SA, Caswell PT, Noll JE, Coffill CR, Lane DP, Sansom OJ, Neilsen PM, Norman JC*, Vousden KH*. Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion. Oncogene 32: 1252-65, 2013 *joint corresponding authors

Jacquemet G, Green DM, Bridgewater RE, von Kriegsheim A, Humphries MJ, Norman JC, Caswell PT. RCP-driven alpha5beta1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex. J Cell Biol 202: 917-35, 2013

Rainero E, Norman JC. Late endosomal and lysosomal trafficking during integrin-mediated cell migration and invasion. BioEssays 35: 523-32, 2013

2012

Christoforides C, Rainero E, Brown KK, Norman JC* and Toker A*. PKD Controls αvβ3 Integrin Recycling and Tumor Cell Invasive Migration Through its Substrate Rabaptin-5. Dev Cell 23: 560-572, 2012 *joint corresponding authors

Dozynkiewicz MA, Jamieson NB, MacPherson I, Grindlay J, van den Berghe P, von Thun A, Morton JP, Gourley C, Timpson P, Nixon C, McKay CJ, Carter R, Strachan D, Anderson K, Sansom OJ, Caswell PT, Norman JC. Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. Dev Cell 17: 131-45, 2012

Rainero E, Caswell PT, Muller PA, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJ, Vousden KH, Graziani A, Norman JC. Diacylglycerol kinase alpha controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol 196: 277-95, 2012

von Thun A, Birtwistle M, Kalna G, Grindlay J, Strachan D, Kolch W, von Kriegsheim A, Norman JC. ERK2 drives tumour cell migration in three-dimensional microenvironments by suppressing expression of Rab17 and liprin-beta2. J Cell Sci 125: 1465-77, 2012

Chen Y, Rice W, Gu Z, Li J, Huang J, Brenner MB, Van Hoek A, Xiong J, Gundersen GG, Norman JC, Hsu VW, Fenton RA, Brown D, Lu HA. Aquaporin 2 Promotes Cell Migration and Epithelial Morphogenesis. J Am Soc Nephrol 23: 1506, 2012

Eva R, Crisp S, Marland JR, Norman JC, Kanamarlapudi V, Ffrench-Constant C, Fawcett JW. ARF6 Directs Axon Transport and Traffic of Integrins and Regulates Axon Growth in Adult DRG Neurons. J Neurosci 32: 10352-64, 2012

Gao M, Patel R, Ahmad I, Fleming J, Edwards J, McCracken S, Sahadevan K, Seywright M, Norman J, Sansom O, Leung HY. SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis. EMBO Mol Med 4: 776, 2012

Margadant C, Kreft M, de Groot DJ, Norman JC, Sonnenberg A. Distinct Roles of Talin and Kindlin in Regulating Integrin alpha5beta1 Function and Trafficking. Curr Biol 22: 1554-63, 2012

Onodera Y, Nam JM, Hashimoto A, Norman JC, Shirato H, Hashimoto S, Sabe H. Rab5c promotes AMAP1-PRKD2 complex formation to enhance beta1 integrin recycling in EGF-induced cancer invasion. J Cell Biol 197: 983-96, 2012

Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman JC, Neufeld G, Tamagnone L Neuropilin-1 dependent regulation of EGF-Receptor signalling. Cancer Research 72(22): 5801-11, 2012

Yu X, Zech T, McDonald L, Garcia-Gonzalez E, Li A Macpherson I, Schwarz J, Spence H, Futo K, Timpson P, Nixon C, Ma Y, Anton IM, Visegrady B, Insall RH, Oien K, Blyth K, Norman JC and Machesky LM. N-WASP coordinates the delivery and F-actin mediated capture of MT1-MMP at invasive pseupodods to drive matrix remodeling and cancer cell invasion. J Cell Biol 199: 527, 2012

Bridgewater R, Norman JC, Caswell PT. Integrin trafficking at a glance. J Cell Science 125: 3695-3701, 2012

Rainero E, van den Berghe P, Norman JC. Internalisation, endosomal trafficking and recycling of integrins during cell migration and cancer invasion. Chapter in: VESICLE TRAFFICKING IN CANCER (Eds. Dr. Yosef Yarden and Dr. Gabi Tarcic). Cancer Research, Springer Science and business media, 2012

2011

Muller PA, Vousden KH, Norman JC (2011). p53 and its mutants in tumor cell migration and invasion. J Cell Biol. 192, 209-18.

Rainero E, Norman JC (2011). New roles for lysosomal trafficking in morphogen gradient sensing. Sci Signal 4, pe24.

Lindsay CR, Lawn S, Campbell AD, Faller WJ, Rambow F, Mort RL, Timpson P, Li A, Cammareri P, Ridgway RA, Morton JP, Doyle B, Hegarty S, Rafferty M, Murphy IG, McDermott EW, Sheahan K, Pedone K, Finn AJ, Groben PA, Thomas NE, Hao H, Carson C, Norman JC, Machesky LM, Gallagher WM, Jackson IJ, Van Kempen L, Beermann F, Der C, Larue L, Welch HC, Ozanne BW, Sansom OJ. P-Rex1 is required for efficient melanoblast migration and melanoma metastasis. Nat Commun doi: 10.1038/ncomms1560, published online 22 Nov 2011

Murdoch H, Vadrevu S, Prinz A, Dunlop AJ, Klussmann E, Bolger GB, Norman JC, Houslay MD (2011). Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function. J Cell Sci. 124, 2253-66.

Zech T, Calaminus SDJ, Caswell PT, Spence HJ, Carnell MJ, Insall RH, Norman JC, Machesky LM. The Arp2/3 activator WASH regulates alpha-5 beta- 1 integrin mediated invasive migration. J Cell Sci doi: 10.1242/ jcs.080986, published online 23 Nov 2011

Margadant C, Monsuur HN, Norman JC, Sonnenberg A. Mechanisms of integrin activation and trafficking. Curr Opin Cell Biol 2011; 23: 607-14

2010

di Blasio L, Droetto S, Norman J, Bussolino F, Primo L (2010). Protein kinase D1 regulates VEGF-A-induced alphavbeta3 integrin trafficking and endothelial cell migration. Traffic 11, 1107-18.

Eva R, Dassie E, Caswell PT, Dick G, ffrench- Constant C, Norman JC, Fawcett JW (2010). Rab11 and its effector Rab coupling protein contribute to the trafficking of beta 1 integrins during axon growth in adult dorsal root ganglion neurons and PC12 cells. J Neurosci. 30, 11654-69.

Kelly EE, Horgan CP, Adams C, Patzer TM, Ni Shuilleabhain DM, Norman JC, McCaffrey MW (2010). Class I Rab11-Family Interacting Proteins are binding targets for the Rab14 GTPase. Biol Cell. 102, 51-62.

2009

Jones MC, Caswell PT, Moran-Jones K, Roberts M, Barry ST, Gampel A, Mellor H, Norman JC (2009). VEGFR1 (Flt1) Regulates Rab4 Recycling to Control Fibronectin Polymerization and Endothelial Vessel Branching. Traffic 10, 754-66.

Moran-Jones K, Grindlay J, Jones M, Smith R, Norman JC (2009). hnRNP A2 Regulates Alternative mRNA Splicing of TP53INP2 to Control Invasive Cell Migration. Cancer Res. 69, 9219-27.

Muller PAJ, Caswell PT, Doyle B, Iwanicki MP,Tan EH, Karim S, Lukashchuk N, Gillespie DA, Ludwig RL, Gosselin P, Cromer A, Brugge JS, Sansom OJ, Norman JC, Vousden KH (2009). Mutant p53 drives invasion by promoting integrin recycling. Cell 139, 1327-41.

Reynolds AR, Hart IR, Watson AR, Welti JC, Silva RG, Robinson SD, Da Violante G, Gourlaouen M, Salih M, Jones MC, Jones DT, Saunders G, Kostourou V, Perron-Sierra F, Norman JC, Tucker GC, Hodivala-Dilke KM (2009). Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. 15, 392-400.

Valdembri D, Caswell PT, Anderson KI, Schwarz JP, Konig I, Astanina E, Caccavari F, Norman JC, Humphries MJ, Bussolino F, Serini G (2009). Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells. PLoS Biol. 7, e25.

Caswell PT, Vadrevu S, Norman JC (2009). Integrins: masters and slaves of endocytic transport. Nat Rev Mol Cell Biol. 10, 843-53.

Mills GB, Jurisica I, Yarden Y, Norman JC (2009). Genomic amplicons target vesicle recycling in breast cancer. J Clin Invest. 119, 2123-7.

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Jim Norman - Integrin Cell Biology

Lab Members

norman lab 2013

Post-docs

Jesica Diaz-Vera
Emmanuel Dornier (Breast Cancer Campaign)
Sergi Marco-Martin
Liane McGlynn (UoG)
Elena Rainero (West of Scotland Women's Bowling Association)

Scientific Officer

Louise Mitchell

Associate Clinical Scientist

Iain MacPherson (CRUK Senior Clinical Fellowship)

PhD Students

Cassie Clarke
Nikki Heath
Nick Rabas
Elena Ruengeler

Research

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Seminars

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