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

Link to Dept of Pathology

Link to Heike Laman (Pathology)

Clare College,
Trinity Lane,
Cambridge CB2 1TL

Link to Clare College

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.

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

In 1997, we cloned the F-box protein, Fbxo7, as an interacting partner for a virally encoded D-type 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 pathologies, including male sterility and anaemia to thymic hypoplasia. In 2008. mutations in Fbxo7 were discovered to be associated with idiopathic and early onset forms of parkinsonism. 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. We are using mouse models and organoid cultures to understand the tissue-specific pathologies.

Learn More

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 are investigating using nanobodies as the ligands in biological PROTACs (PRoteolysis TArgeting Chimeras)., and we collaborate with AstraZeneca in some of the design of some of our PROTACs.

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.

Deregulated SCF networks in epithelial cancers.

We are investigating Fbxw7-cyclin E and replication stress in breast and ovarian cancer. In a collaborative project with AstraZeneca, we are looking at the responsiveness of particular subtypes of breast cancers to checkpoint inhibitors. .

Publications, Datasets, & Reagents

Restoration of Fbxo7 expression in dopaminergic neurons restores tyrosine hydroxylase in a mouse model of Parkinson’s disease. Al Rawi S, Tyers P, Barker RA, Laman H. biorxiv 2024 Oct. Link.
Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co-regulate proteasomes and mitochondria. Al Rawi S*, Simpson L*, Agnarsdóttir G, McDonald NQ, Chernuha V, Elpeleg O, Zeviani M, Barker RA, Spiegel R^, Laman H.^ FEBS J 2024 Feb. Link.
- Comment on our article. Link.
Development of constrained peptide inhibitors targeting an oncogenic E3 ubiquitin ligase. Zenkevičiūtė G, Xu W, Iegre J, Seki H, Tan YS, Rowling PJE, Ferrer F, Verma C, Spring DR, Laman H, Itzhaki LS. biorxiv 2023 May. Link
E3 Ubiquitin Ligases: From Structure to Physiology to Therapeutics, Volume II. Licchesi J, Laman H, Ikeda F, Ferguson F. Bolanos-Garcia V. Front Physiol. 2022. doi.org/10.3389/fphys.2022.1038793 . eCollection. Link.
Fbxo7 promotes Cdk6 activity to inhibit PFKP and glycolysis in T cells. Harris R, Yang M, Schmidt C, Royet C, Singh S, Natarajan A, Morris M, Frezza C, Laman H. J Cell Biol. 2022 Jun 7. doi: 10.1083/jcb.202203095. Link. Spotlight on our article. Link.
- J Cell Biol: Article Spotlight: Ubiquitinating the way to T cell metabolism. McPhedran S & Lum J. 2022 Jun 13. Link.
- Metabolomics dataset available on Metabolomics Workbench. Link .Study ID ST001986 (DatatrackID:2912).
A FBXO7/EYA2-SCFFBXW7 axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells. Shen JZ, Qiu Z, Wu Q, ZhangG, Harris R, Sun D, Rantala J, Barshop WD, Zhao L, Lv D, Won KA, Wohlschlegel J, Sangfelt O, Laman H, Rich JN, Spruck C. Mol Cell. Mar 17;82(6):1123-1139.e8. doi: 10.1016/j.molcel.2022.01.022. Epub 2022 Feb 18. Link.
Laman Lab Plamids available on Addgene! Link.
Analysis of the FBXO7 promoter reveals overlapping Pax5 and c-Myb binding sites functioning in B cells. Harris R, Randle SJ, Laman H. Biochem Biophys Res Comm 2021 Mar 11.doi: 10.1016/j.bbrc.2021.03.052. Epub 2021 Mar 25. Link.
The FBXL family of F-box proteins: variations on a theme. Mason BJ & Laman H. Open Biol. 2020 Nov;10(11):200319. doi: 10.1098/rsob.200319. Epub 2020 Nov 25. Link.

E3 Ubiquitin Ligases: From Structure to Physiology. Licchesi JDF, Laman H, Ikeda F, Bolanos-Garcia VM. Front Physiol. 2020. Nov 26;11:621053. doi: 10.3389/fphys.2020.621053. eCollection.. Link.
The E3 ubiquitin ligase SCF(Fbxo7) mediates proteasomal degradation of UXT isoform 2 (UXT-V2) to inhibit the NF-kappa B signaling pathway. Spagnol V, Oliveira CAB, Randle SJ, Passos PMS, Correia CRSTB, Simaroli NB, Oliveira JS, Mevissen TET, Medeiros AC, Gomes MD, Komander D, Laman H, Teixeira FR. Biochim Biophys Acta. 2020 Sep 30;1865(1):129754. doi: 10.1016/j.bbagen.2020.129754. Link.
Nedd8 hydrolysis by UCH proteases in Plasmodium parasites. Karpiyevich M, Adjalley S, Mol M, Ascher DB, Mason B, van der Heden van Noort GJ, Laman H, Ovaa H, Lee MCS, Artavanis-Tsakonas K. PLoS Pathog. 2019 Oct 28;15(10):e1008086. doi: 10.1371/journal.ppat.1008086. Link. PDF.
A conserved requirement for Fbxo7 during male germ cell cytoplasmic remodelling. Rathje CC, Randle SJ, Al Rawi S, Skinner BM, Rajamundar A, Nelson DE, Johnson EEP, Bacon J, Vlazak M, Affara NA, Ellis PJ, Laman H. Front Physiol. 2019. Oct 10;10:1278. doi: 10.3389/fphys.2019.01278. Link. PDF.
Fbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation. Mason B, Flach S, Teixeira, FR, Manzano Garcia R, Rueda OM, Abraham JE, Caldas C, Edwards PAW. Laman H. Cell Mol Life Sci. 2019 Sept 27. Link. PDF.
Loss of FBXO7 results in a Parkinson’s-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway. Stott SRW*, Randle SJ*, al Rawi S, Rowicka PA, Harris R, Mason B, X.ia J, Dalley, JW, Barker RA, Laman H. J Pathol. 2019 Oct;249(2):241-254. Link. PDF.

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. 2017 Apr;74(8):1553-1566 . Link. PDF
Structure and function of Fbxo7/PARK15 in Parkinson's disease. Randle SJ, Laman H. Curr Protein Pept Sci. 2017;18(7):715-724. 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.
F-box protein interactions with the hallmark pathways in cancer. Randle SJ, Laman H. Semin Cancer Biol. 2016 Feb;36:3-17. Link. PDF.
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 Jun;237:263-272. Link. PDF. Supp.

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.
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.
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.
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

Professor Heike Laman

Heike Laman is the Head of the Department of Pathology and a Professor in Cellular and Molecular Biology. https://www.path.cam.ac.uk/. She was awarded her BSc. 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 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 heterochromatin assembly in Saccharomyces cerevisiae.

Prof 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 Prof Nic Jones from 1997-1999, and 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 Prof Chris Boshoff at the Wolfson Institute for Biomedical Research at University College London from 2001-2005.

In 2005, Professor Laman was awarded her independent Research Fellowship to join the Department of Pathology at the University of Cambridge. She was elected to the Fellowship of Clare College in 2014 and is Director of Studies in Pathology and Genetics, Graduate Admissions Tutor, and Trustee of the College.

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 opportunities to join our lab.

Current Members

Finn Snow

Finn joined the lab in October 2024 to begin his MRC-ITTP-funded PhD studentship in collaboration with AstraZeneca in targeted protein degradation and ubiquitination. He graduated from the University of Bath with a first class BSc. degree in Biochemistry, spending a placement year at GSK working on protein target generation. Since developing a passion for pharmaceutical research, he completed a MSc. Drug Design degree (distinction) from University College London, where his project focused on developing a small molecule diagnostic for alpha-1 antitrypsin deficiency. His PhD research will mainly focus on understanding the unique off-target mechanisms of Proteolysis Targeting Chimeras (PROTACs).

Sara al Rawi

Born in Paris, Sara joined the lab in 2018 to start a Parkinson's UK-funded research project investigating the neuroprotective roles of Fbxo7 with a focus on an early stages of Parkinson's disease. Previously, Sara obtained a Master degree in cellular and molecular biology with a specialization in proteomics from the Pierre and Marie Curie University, in Paris. After being awarded her degree, Sara began working as a research assistant to investigate how sperm derived mitochondria are degraded in the early embryo using C. elegans as a model. This work led to the discovery of the autophagy pathway in this specific degradation event. Sara was awarded an AXA-Academie des Sciences award from the French Science academy for her work. Her PhD research was under the supervision of Dr Vincent Galy at the Pierre and Marie Curie University and focussed on discovering how sperm-derived mitochondria are specifically recognized and targeted by the autophagy machinery.

Sophie Willis

Sophie joined the lab in October 2020 to start a PhD investigating the role of ubiquitination in different subtypes of Cyclin E high cancers. She graduated from the University of Leeds in 2016 with a Bachelor of Science (Hons) in Genetics (Industrial), spending her placement year at MedImmune investigating immune cell populations in pancreatic cancer using immunohistochemistry and NanoString gene expression assays. Since graduating, she has worked at AstraZeneca, developing immunohistochemistry and RNA in situ hybridisation assays to support pharmacodynamic assessments and patient selection strategies on a range of clinical projects.

Hanna Bjone

Hanna joined the lab in October 2021 to start her PhD funded by Aker Scholarship (Norway) to investigate the neuroprotective effects of Fbxo7 in Parkinson's disease focusing on its effects on Cdk6 activity and intracellular trafficking. Born in Oslo, Hanna moved to the UK for her undergraduate studies and graduated from Durham University with a first class integrated Master’s degree in biological sciences. Her final year project focused on the production and optimization of recombinant insecticidal fusion proteins. Prior to coming to Cambridge, she spent a year at the University of Oslo completing a course in computer science in bioinformatics.

Guðrún Diljá Agnarsdóttir

Guðrún started in the lab in October 2022 for her MPhil and is continuing now to study for her PhD. She is investigating the ubiquinome of the pathogenic missense mutation L250P in Fbxo7, which is associated with atypical parkinsonism. She graduated in 2022 from the University of Iceland with a first class BSc degree in Biochemistry and Molecular Biology. During the final year of her degree, she worked as a research associate in the Biological Materials Facility at deCODE Genetics in Iceland. Guðrún also completed her undergraduate dissertation project at deCODE, using their vast amount of omics data to examine the phenotypic impact of rare genetic variants in the human CYP2R1 gene.

Libby Wiseman

Libby joined the lab in October 2023 to begin her PhD, investigating the utility of nanobodies and targeted protein degradation in novel biological therapies for Myc driven cancers, such as neuroblastoma. She graduated in 2018 from Oxford Brookes University with a first class Bachelor of Science (Hons) degree in Biomedical Science, where her final year project focused on cellular senescence following radiotherapy. In 2021, Libby became a Scientist at AstraZeneca, where she works on validation of new cancer biomarkers using translational techniques such as immunohistochemistry, with the aim to achieve better understanding of patient response to treatment and mechanisms of resistance.

Min Zhang

Min joined the lab in February 2024 to start a postdoc research on how do Fbxo7 and PI31 control sperm morphogenesis and male fertility. Previously, Min obtained a Master degree in Clinical Veterinary Medicine focusing on nutritional and metabolic diseases in perinatal dairy cows at Jilin University, China. Min moved to The Netherlands in October 2016 and started her PhD in Biochemistry and Reproductive Biology at Utrecht University. Her PhD research characterized the involvement of CRISP2 in the organization of dense protein structures in porcine sperm.