Jim Norman - Integrin Cell Biology

Introduction

norman j

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.

 
Other funding:
                     West of Scotland Womens Bowling logo

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

2017

Diaz-Vera J, Palmer S, Hernandez-Fernaud JR, Dornier E, Mitchell LE, MacPherson I, Edwards J, Zanivan S, Norman JC. A proteomic approach to identify endosomal cargoes controlling cancer invasiveness. J Cell Sci 2017; 130: 697-711

Dornier E, Rabas N, Mitchell L, Novo D, Dhayade S, Marco S, Mackay G, Sumpton D, Pallares M, Nixon C, Blyth K, MacPherson I, Rainero E, Norman JC. Glutaminolysis drives membrane trafficking to promote cancer invasion. Nat Comms 2017; 8: 2255

Gundry C, Marco S, Rainero E, Miller B, Dornier E, Mitchell L, Caswell PT, Campbell AD, Hogeweg A, Sansom OJ, Morton JP, Norman JC. Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion. Nat Commun 2017; 8: 14646

Hall PS, Smith A, Hulme C, Vargas-Palacios A, Makris A, Hughes-Davies L, Dunn JA, Bartlett JMS, Cameron DA, Marshall A, Campbell A, Macpherson IR, Dan Rea, Francis A, Earl H, Morgan A, Stein RC, McCabe C; OPTIMA Trial Management Group. Value of information analysis of multiparameter tests for chemotherapy in early breast cancer: The OPTIMA Prelim Trial. Value Health 2017; 20: 1311-8

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

Dornier E, Norman JC. Tensin links energy metabolism to extracellular matrix assembly. J Cell Biol 2017; 216: 867-9

Norman J, Zanivan S. Chloride intracellular channel 3: A secreted pro-invasive oxidoreductase. Cell Cycle 2017; 16: 1993-4

2016

Birch J, Clarke CJ, Campbell AD, Campbell K, Mitchell L, Liko D, Kalna G, Strathdee D, Sansom OJ, Neilson M, Blyth K, Norman JC. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma. Biol Open 5: 1371-9, 2016

Boulay PL, Mitchell L, Turpin J, Huot-Marchand JE, Lavoie C, Sanguin-Gendreau V, Jones L, Mitra S, Livingstone JM, Campbell S, Hallett M, Mills GB, Park M, Chodosh L, Strathdee D, Norman JC, Muller WJ. Rab11-FIP1C is a critical negative regulator in ErbB2-mediated mammary tumor progression. Cancer Res 76: 2662-74, 2016

Clarke CJ, Berg TJ, Birch J, Ennis D, Mitchell L, Cloix C, Campbell A, Sumpton D, Nixon C, Campbell K, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Jones JL, Haywood L, Pulleine E, Yin HB, Strathdee D, Sansom O Blyth K, McNeish I, Zanivan S, Reynolds AR, Norman JC. The initiator methionine tRNA drives secretion of type II collagen from stromal fibroblasts to promote tumor growth and angiogenesis. Curr Biol 26: 755-65, 2016

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

Images

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Jim Norman - Integrin Cell Biology

Lab Members

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Post-docs

Emmanuel Dornier
Sergi Marco-Martin
Madeleine Moore
Sarah Palmer (West of Scotland Women's Bowling Association Fellow)
Luis Pardo-Fernandez

Principal Scientific Officer

Louise Mitchell

Associate Clinical Scientist

Iain MacPherson

Clinical Research Fellow

Dominik Koessinger

PhD Students

David Novo
Nick Rabas

Research

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Seminars

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