Ubiquitin has emerged as a key regulatory protein for signaling pathways by modulating signaling outputs in the cell. This post-translational modification creates versatility in cell signaling due to its capacity to form eight different inter-ubiquitin linkages through the seven lysine residues of ubiquitin and through its N-terminal methionine (M1) The latter, referred to as linear or M1 linkage, is created by the linear ubiquitin chain assembly complex (LUBAC), the sole E3 ligase known to date that is capable of forming linear ubiquitin chains de novo. The role of LUBAC and linear ubiquitin chains is evident in immune and cell death signaling, but their role in tumor-driving signaling pathways is ill-defined. Therefore, I aim to assess the contribution of LUBAC and linear ubiquitination in tumorigenic signaling, with the ultimate goal to provide novel opportunities for interfering with aberrant cancer signaling.
After graduating Biomedical Sciences (BSc, MSc) at Utrecht University I joined the lab of Prof. Madelon M. Maurice (UMC Utrecht) for my PhD to study the regulation of the Wnt signaling pathway, a signaling cascade vital in development but also in adult tissue homeostasis. We discovered novel modes of Wnt pathway regulation, including ubiquitination, which triggered my interest in this highly versatile post-translational modification. Therefore, after obtaining my PhD, I joined the lab of Prof. Henning Walczak (UCL Cancer Institute, London, UK) to study the role of linear ubiquitination in tumorigenic signaling, which was supported by a KWF (Dutch Cancer Society) fellowship. Currently, I am performing the second part of this fellowship in the lab of Prof. Peter ten Dijke and continue to study the role of linear ubiquitination in cancer signaling.
Linear ubiquitination at a glance.
Spit M, Rieser E, Walczak H.
J Cell Sci. 2019 Jan 18;132(2). pii: jcs208512. doi: 10.1242/jcs.208512.
Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer.
Spit M, Koo BK, Maurice MM.
Open Biol. 2018 Sep 12;8(9). pii: 180120. doi: 10.1098/rsob.180120.
Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors.
Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJ, Maurice MM, Clevers H.
Nature. 2012 Aug 30;488(7413):665-9. doi: 10.1038/nature11308.