Steve Ley

Immune Cell Signalling laboratory

Following infection, pathogenic microorganisms such as viruses and bacteria are initially recognised by specific receptors on the surface of neutrophils and macrophages. This triggers an immediate 'innate' immune response involving the production of proteins called chemokines and cytokines. These attract other immune cells to the sites of infection (inflammation) and also initiate the adaptive immune response that culminates in the production of protective antibodies and killing of infected cells.

The major focus of my group is to study a key MAP kinase signalling pathway activated during innate immune responses that is regulated by the protein kinase TPL-2 (Figure 1).

Figure 1

Figure 1: The IKK / TPL-2 MAP kinase pathway. (Click to view larger image)

Our current experiments are investigating the mechanism of TPL-2 activation by pathogen infection, and how TPL-2 regulation of cytokine and chemokine production in innate immune cells regulates inflammatory responses. In a new area of research for the laboratory (done in collaboration with Anne Bowcock at Imperial College London), we are also researching how the adaptor protein CARD14 activates NF-kB to trigger inflammation in the skin (Figure 2). Mutations in the gene encoding CARD14 lead to a high risk of developing psoriasis and psoriatic arthritis.

Figure 2

Figure 2: Model of psoriasis pathogenesis induced by CARD14 signalling. (Click to view larger image)

Selected publications

Pattison MJ, Mitchell O, Flynn HR, Chen CS, Yang HT, Ben-Addi H, Boeing S, Snijders AP, Ley SC (2016) TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase. Biochem J. Sep 15;473(18):2845-61. doi: 10.1042/BCJ20160502.PMID: 27402796 PubMed abstract

Howes A, O'Sullivan PA, Breyer F, Ghose A, Cao L, Krappmann D, Bowcock AM, Ley SC (2016) Psoriasis mutations disrupt CARD14 autoinhibition promoting BCL10-MALT1-dependent NF-κB activation.  Biochem J. Jun 15;473(12):1759-68. doi: 10.1042/BCJ20160270. PMID: 27071417 PubMed abstract

Jacque, E; Schweighoffer, E; Tybulewicz, VLJ and Ley, SC (2015) BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival. Journal of Experimental Medicine 212, 883-892 PubMed abstract

Jacque, E; Schweighoffer, E; Visekruna, A; Papoutsopoulou, S; Janzen, J; Zillwood, R; Tarlinton, DM; Tybulewicz, VLJ and Ley, SC (2014) IKK-induced NF-κB1 p105 proteolysis is critical for B cell antibody responses to T cell-dependent antigen. Journal of Experimental Medicine 211, 2085-2101 PubMed abstract

Steve Ley

Steve Ley

steve.ley@crick.ac.uk
+44 (0)20 379 62207

  • Qualifications and History
  • 1987 PhD Department of Pathology, University of Cambridge
  • 1987 - 1990  Post-doctoral Fellow, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
  • 1990 - 1992 Post-doctoral Fellow, Imperial Cancer Research Fund, London, UK
  • 1992 - 2015 Group Leader, MRC National Institute for Medical Research, London, UK
  • 2015 - Group Leader, The Francis Crick Institute, London, UK