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Welcome to the Laman Lab

 

 

The Laman Lab's mission is to understand and devise novel treatments for diseases caused by deregulation of ubiquitin ligases.

 

Research in our lab focuses on the study of ubiquitin ligases.  They are remarkably multi-functional proteins and touch on aspects of biology ranging from development and regulation of the cell cycle to the immune system and cell signalling.  Given such central roles, their malfunctioning is linked with many pathologies, such as cancer, neurodegenerative, and infectious diseases.  Our research has branched into many diverse areas, including developing novel therapeutics against ubiquitin ligases, but our focus on these enigmatic enzymes is the common link for our group.

 

Our laboratory is based on the Downing Site in Tennis Court Road in central Cambridge with access to the nearby Institutes and Departments in the School of Biological Sciences, the city centre and the Colleges. 

 

 

Phone

+44 (0)1223 333722

Email

hl316@cam.ac.uk

 

Locations

Department of Pathology,
Division of Cellular and Molecular Pathology,
University of Cambridge Tennis Court Road
Cambridge CB2 1QP

Clare College,
Trinity Lane,
Cambridge CB2 1TL

 

 

 

Research

 

Ubiquitin ligases are enzymes that decorate proteins in the cell with ubiquitin, a relatively large (76aa) peptide.  This modification with ubiquitin on a protein can signal many different things to the target substrate,  A well-described effect brought about by ubiquitination is that it changes a protein's stability, but other effects include changes to localisation, intracellular trafficking, binding partners, and function. My laboratory is particularly intrigued by these 'alternate' ubiquitin-mediated signals.  We are also interested in ubiquitin signalling within different cellular contexts, as we have discovered ubiquitin networks vary from tissue to tissue and use mouse models to study the molecular basis for this.  We want to understand the dynamic nature and complexity of ubiquitin signalling, and invent novel therapeutics exploiting ubiquitin ligase enzymology and their critically regulated pathways.  

 
 
 
H&E staining of spleen sections from mice deficient in expression of Fbxo7.

H&E staining of spleen sections from mice deficient in expression of Fbxo7.

The biology of Fbxo7/PARK15: from anaemia to cancer to Parkinson's disease.

In 1997, we cloned the F-box protein, Fbxo7, as an interacting partner for a herpesvirus-encoded viral cyclin.  We have since created multiple mouse models that are deficient in the expression of Fbxo7 either in the whole mouse or in specific tissues.  We investigate the numerous disease, including anaemia and cancer, seen in multiple tissues, ranging from both B and T lymphocytes to red blood cells.  In 2008. mutations in Fbxo7 were discovered to be associated with idiopathic and early onset forms of Parkinson's disease.  We also investigate the loss of its expression in dopaminergic neurons, the cells that are lost in this disease.  We are investigating the molecular basis for the different pathways regulated by Fbxo7 that cause these pathologies in various cell types. 

 
Engineering better protein interactions using the diversity of the immune system (A) or structurally informed, conformationally constrained peptides (B).

Engineering better protein interactions using the diversity of the immune system (A) or structurally informed, conformationally constrained peptides (B).

Targeting ubiquitin ligases and ubiquitinated proteins with novel biotherapeutic approaches.

The discovery of camelid-derived antibodies known as nanobodies offers researchers all the specificity and affinities of conventional antibodies in a compact, highly-stable domain, known as a nanobody.  We use nanobodies to define and test the functional significance of interactions between ubiquitin ligases and their substrates. We collaborate with Serge Muyldermans to produce nanobodies.

We also are investigating the possibility of specifically interfering with the capacity of ubiquitin ligases to modify their substrates.  Based on structural information, we collaborate with Laura Itzhaki and David Spring in the production of stapled peptides that mimic the conformation of docked substrates in ubiquitin ligases and test the biochemical and cellular effects of stapled peptides on the ubiquitin ligases.

 
Purified active SCF-ligases used on protein arrays to identify networks of ubiquitinated substrates.

Purified active SCF-ligases used on protein arrays to identify networks of ubiquitinated substrates.

Deregulated SCF networks in epithelial cancers.

We are investigating the consequences of the rearrangement of two F-box genes in breast cancer.  We are doing a biochemical analysis of the effect of the mutations on the ligases and on the pathways that they regulate using proteome wide approaches, including protein arrays, mass spectrometry, and yeast two hybrid screens. Specific substrates and the critical pathways that are deregulated are being defined, and their role in oncogeneisis studied.

 

Publications


2016

  • Opposing effects on the cell cycle of T lymphocytes by Fbxo7 via Cdk6 and p27. Patel SP, Randle SJ, Gibbs S, Cooke A, Laman H. Cell Mol Life Sci. 2016 Dec 3. Link. PDF

  • Gsk3β and Tomm20 are substrates of the SCF-Fbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease. Teixeira FR^, Randle SJ^, Patel SP^, Mevissen TE, Zenkeviciute G, Koide T, Komander D, Laman H. Biochem J. 2016 Oct 15;473(20):3563-3580. ^First author. Link. PDF. Supp.

  • Structure and function of Fbxo7/PARK15 in Parkinson's disease. Randle SJ, Laman H. Curr Protein Pept Sci. 2016 Mar 11. Link. PDF

  • F-box protein interactions with the hallmark pathways in cancer. Randle SJ, Laman H. Semin Cancer Biol. 2016 Feb;36:3-17. Link. PDF

2015

  • Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression. Randle SJ, Nelson DE, Patel SP, Laman H. J Pathol. 2015 Oct;237(2):263-72. Link. PDF. Supp.

2013

  • Beyond ubiquitination: the atypical functions of Fbxo7 and other F-box proteins. Nelson DE, Randle SJ, Laman H. Open Biol. 2013 Oct 9;3(10):130131. Link. PDF
  • The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Burchell VS^, Nelson DE^, Sanchez-Martinez A^, Delgado-Camprubi M, Ivatt RM, Pogson JH, Randle SJ, Wray S, Lewis PA, Houlden H, Abramov AY, Hardy J, Wood NW, Whitworth AJ*, Laman H*, Plun-Favreau H*. Nat Neurosci. 2013 Sep;16(9):1257-65. ^First author; *Senior corresponding author. Link. PDF.
    • Comment: Daily Mail. Link
    • Comment: University of Cambridge press release. Link
    • Comment: Alzheimer's Forum. Link
    • Comment: Recommended on F1000
    • Comment: Parkinson's News Today. Link.
    • Highlight: Degenerating Neurons. Link.

2012

  • Identification of F-box only protein 7 as a negative regulator of NF-kappaB signalling. Kuiken HJ, Egan DA, Laman H, Bernards R, Beijersbergen RL, Dirac AM. J Cell Mol Med. 2012 Sep;16(9):2140-9. Link. PDF
  • Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA. Gooding M, Tudzarova S, Worthington RJ, Kingsbury SR, Rebstock AS, Dube H, Simone MI, Visintin C, Lagos D, Quesada JM, Laman H, Boshoff C, Williams GH, Stoeber K, Selwood DL. Chem Biol Drug Des. 2012 Jan;79(1):9-21. Link. PDF

2011

  • Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis. Lomonosov M, Meziane el K, Ye H, Nelson DE, Randle SJ, Laman H. PLoS One. 2011;6(6):e21165. Link. PDF
  • Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells. Meziane el K^, Randle SJ^, Nelson DE, Lomonosov M, Laman H. J Cell Sci. 2011 Jul 1;124(Pt 13):2175-86. ^First author. Link. PDF
  • A Competitive binding mechanism between Skp1 and exportin 1 (CRM1) controls the localization of a subset of F-box proteins. Nelson DE, Laman H. J Biol Chem. 2011 Jun 3;286(22):19804-15. Link. PDF

Older

  • Structure of a conserved dimerization domain within the F-box protein Fbxo7 and the PI31 proteasome inhibitor. Kirk R, Laman H, Knowles PP, Murray-Rust J, Lomonosov M, Meziane el K, McDonald NQ. J Biol Chem. 2008 Aug 8;283(32):22325-35. Link. PDF
  • Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells.Okuyama M^, Laman H^, Kingsbury SR^, Visintin C, Leo E, Eward KL, Stoeber K, Boshoff C, Williams GH, Selwood DL. ^First author. Nat Methods. 2007 Feb;4(2):153-9. Link. PDF
    • Comment: Research highlights in Nature. Link.
    • Comment: Spotlight in ACR Chemical Research. Link.
  • Fbxo7 gets proactive with cyclin D/cdk6. Laman H. Cell Cycle. 2006 Feb;5(3):279-82. Link. PDF
  • Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6. Laman H, Funes JM, Ye H, Henderson S, Galinanes-Garcia L, Hara E, Knowles P, McDonald N, Boshoff C. EMBO J. 2005 Sep 7;24(17):3104-16. Link. PDF
  • Regulation of growth signalling and cell cycle by Kaposi's sarcoma-associated herpesvirus genes. Direkze S, Laman H. 2004 Dec;85(6):305-19. Link. PDF
  • RNA interference: a potential tool against Kaposi's sarcoma-associated herpesvirus. Godfrey A, Laman H, Boshoff C. Curr Opin Infect Dis. 2003 Dec;16(6):593-600. Link.
  • Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Coverley D, Laman H, Laskey RA. Nat Cell Biol. 2002 Jul;4(7):523-8. Link. PDF
  • Cyclin-mediated export of human Orc1. Laman H, Peters G, Jones N. Exp Cell Res. 2001 Dec 10;271(2):230-7. Link. PDF
  • Is KSHV lytic growth induced by a methylation-sensitive switch? Laman H, Boshoff C. Trends Microbiol. 2001 Oct;9(10):464-6. Link. PDF
  • Viral cyclin-cyclin-dependent kinase 6 complexes initiate nuclear DNA replication. Laman H, Coverley D, Krude T, Laskey R, Jones N. Mol Cell Biol. 2001 Jan;21(2):624-35. Link. PDF
  • Crystal structure of a gamma-herpesvirus cyclin-cdk complex. Card GL, Knowles P, Laman H, Jones N, McDonald NQ. EMBO J. 2000 Jun 15;19(12):2877-88. Link. PDF
  • Viral-encoded cyclins. Laman H, Mann DJ, Jones NC. Curr Opin Genet Dev. 2000 Feb;10(1):70-4. Link. PDF
  • Modulation of p27(Kip1) levels by the cyclin encoded by Kaposi's sarcoma-associated herpesvirus.Mann DJ, Child ES, Swanton C, Laman H, Jones N. EMBO J. 1999 Feb 1;18(3):654-63. Link. PDF
  • Disturbance of normal cell cycle progression enhances the establishment of transcriptional silencing in Saccharomyces cerevisiae. Laman H, Balderes D, Shore D. Mol Cell Biol. 1995 Jul;15(7):3608-17. Link. PDF
  • Identification of a nitrogen-regulated promoter controlling expression of Klebsiella pneumoniae urease genes. Collins CM, Gutman DM, Laman H. Mol Microbiol. 1993 Apr;8(1):187-98. Link.

PI Biography

 

Dr. Heike Laman

Heike Laman was awarded her B.Sc. from the University of Miami in 1990, majoring in Microbiology & Immunology with a double minor in Chemistry and Biology. She graduated cum laude, with General Honors, and was a elected a member of Phi Beta Kappa and Phi Beta Phi.

Prior to starting her PhD studies, she worked as a research assistant with Dr. Carleen Collins.  Here she sequenced the entire urease operon in Klebsiella pneumoniae and discovered the promoter elements controlling its expression. 

She earned her MA, MPhil and Ph.D. degrees from Columbia University in 1992, 1994, and 1997, respectively. Her graduate studies were supervised by Dr. David Shore at Columbia University in the Department of Microbiology & Immunology, researching heterchromatin assembly in Saccharomyces cerevisiae

Dr. Laman emigrated to the United Kingdom in 1997 to undertake post-doctoral research. She was awarded a Research Fellowship from the Imperial Cancer Research Fund in London to work on virally-encoded cyclins with Dr. Nic Jones from 1997-1999, and when he moved to Manchester, she continued her research in the Cell Cycle Regulation laboratory of Dr. Gordon Peters, from 1999-2001. She was awarded a project grant by the Association for International Cancer Research working as a Senior Research Fellow in the Viral Oncology laboratory of Dr. Chris Boshoff at the Wolfson Institute for Biomedical Research at University College London.

In 2005, Dr. Laman was awarded a Research Fellowship and appointed as a Senior Research Associate in the Department of Pathology at the University of Cambridge.  She became a University Lecturer in 2007, and was elected to the Fellowship of Clare College in 2014. 

Our Team

We are always seeking talented, enthusiastic, and curious minds to join our group. Post-doctoral candidates are encouraged to get in touch, sending your CV, to enquire about possibilities,

We have a position open for a PhD student starting in October 2018.  This is a BBSRC-funded Targeted Studentship. The deadline for applications is December 6, 2017. Apply here.

 
 

Current Lab Members

Paulina Rowicka

Paulina joined the lab in October 2013 to start her PhD investigating the role of Fbxo7 in neuronal physiology and neurodegeneration, with a focus on Parkinson’s disease. Previously, She graduated from the University of Utrecht with a BSc (Hons) in Biomedical Sciences and a MSc (Hons) in Experimental and Clinical Neuroscience. She completed her undergraduate research thesis at the Organization for the Prohibition of Chemical Weapons laboratory (Dr Gary Mallard). Paulina spent the first year of her Master’s researching candidate genes and epidemiological factors of Amyotrophic Lateral Sclerosis at the University Medical Centre Utrecht (Prof Leonard van den Berg lab). For her main MSc thesis project, Paulina worked on developing novel transgenic drosophila and human cell line models for the study of tauopathies at the Department of Physiology, Anatomy and Genetics at the University of Oxford (Prof Richard Wade-Martins lab). Prior to starting her PhD, she worked as a research assistant characterizing electrophysiological properties of striatal cholinergic interneurons at the Neurobiology Research Unit of the Okinawa Institute of Science and Technology (Prof Jeff Wickens lab).

 

 

Lisa Kent

Lisa joined the lab in 2014 as a student of the Wellcome Trust PhD Programme in Infection, Immunity and Inflammation (inc. MRes). Prior to her PhD, Lisa received a first class BSc (Hons) degree in Medical Biochemistry with Industrial Experience from the University of Manchester. Her placement year was spent at Boehringer Ingelheim in Biberach, Germany where she tested compounds to treat allergic asthma. During her MRes year, Lisa worked on a range of projects across Cambridge in the field of immunology ranging from autoimmunity to immuno-oncology. She currently works on the characterisation, development and validation of nanobodies targeted against cancer-relevant proteins and is also exploring novel ways to deliver nanobodies therapeutically. Lisa has a strong interest in pharmaceutical development and the commercialisation of her scientific ideas.

 

 

Grasilda Zenkeviciute

Grasilda is a 2nd year PhD student working on an interdisciplinary project funded by Cambridge Cancer Centre. She is developing constrained peptides to target an oncogenic E3 ligase and her work is done in close collaboration with Dr Itzhaki in Pharmacology department. Before joining the lab in October 2015 Grasilda graduated from the University of Edinburgh with a First Class masters degree with honours in Medicinal and Biological Chemistry. She spent her placement year at European Molecular Biology Laboratory (Hamburg) in Matthias Wilmanns' lab working on structural and functional analysis of Type VII secretion system proteins. During her time in Edinburgh Grasilda was awarded Amgen and BBSRC scholarships to carry out summer projects in Karolinska Institute and the University of Oxford. In her free time Grasilda enjoys the great outdoors and goes hiking around UK and Europe.

 
DSC00388.JPG

Bethany Mason

Born in Scarborough, North Yorkshire, Bethany graduated from The University of Manchester in 2015 with a Bachelor of Science (Hons) in Biomedical Sciences with Industrial/Professional Experience. Bethany spent her placement year at The University of Copenhagen, Denmark, where she carried out a research project studying chromatin dynamics in fission yeast. Her final year undergraduate research project focused on the role of micro-RNAs in the maturation and activation of macrophages in diabetes. Bethany joined the lab in January 2016 to begin a four year PhD looking at F-box proteins and their role in breast cancer.

 
 

Past Lab Members

Dr. Suzanne Randle. Suzie is a post-doctoral research fellow at the Cambridge Institute for Medical Research, UK.

Dr. Suzanne Randle.

Suzie is a post-doctoral research fellow at the Cambridge Institute for Medical Research, UK.

 
Dr. Shachi Patel. Shachi is Director of Spykd Ltd, consulting for Navigant Life Sciences, based in London, UK.

Dr. Shachi Patel.

Shachi is Director of Spykd Ltd, consulting for Navigant Life Sciences, based in London, UK.

 
Dr. Felipe Teixeira Felipe is Principal Investigator in Cellular Biochemistry at the Department of Genetics and Evolution at the Federal University of Sao Carlos in Brazil.

Dr. Felipe Teixeira

Felipe is Principal Investigator in Cellular Biochemistry at the Department of Genetics and Evolution at the Federal University of Sao Carlos in Brazil.

 
Dr. David Nelson Dave is an Associate Professor at Middle Tennesee State University in the USA.

Dr. David Nelson

Dave is an Associate Professor at Middle Tennesee State University in the USA.

 
Dr. El Kahina Meziane Kahina is a Teaching Associate at the International School in London, UK.

Dr. El Kahina Meziane

Kahina is a Teaching Associate at the International School in London, UK.

 
Dr. Mikhail Lomonsov Mikhail is Deputy Director of IVIX Ltd. and working for Bioprocess Capital Partners, LLC in Moscow, Russia.

Dr. Mikhail Lomonsov

Mikhail is Deputy Director of IVIX Ltd. and working for Bioprocess Capital Partners, LLC in Moscow, Russia.

 
 

Collaborators

Prof. Roger Barker: Department of Clinical Neurosciences, University of Cambridge, Link.

Dr. Erwin de Genst: AstraZeneca, Discovery Science, AstraZeneca. Link.

Dr. Paul Edwards: Department of Pathology, University of Cambridge. Link.

Prof Gerard Evan: Department of Biochemistry, University of Cambridge. Link.

Dr. Laura Itzhaki: Department of Pharmacology, University of Cambridge. Link.

Prof. Kathryn Lilley: Department of Biochemistry, University of Cambridge. Link.

Dr. David Komander: Laboratory of Molecular Biology, Cambridge. Link.

Prof. Serge Muyldermans: Vrije Universiteit Brussel, Belgium. Link.

Dr. David Spring: Department of Chemistry, University of Cambridge. Link.

Prof Felipe Teixeira: Department of Genetics and Evolution, Universidad Federal Sao Carlos. Link.

Prof Massimo Zeviani: Mitochondrial Biology Unit, Cambridge Institute for Biomedical Research. Link.

 

 

 

 

 

Contact Us

 
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Laman Lab

University of Cambridge

Department of Pathology

Tennis Court Road

Cambridge CB2 1QP

United Kingdom