Investigating regulatory roles of deubiquitylases in cancer-associated Hippo signaling.

This project is jointly supervised by Prof Coulson (Liverpool) and Dr Chan/Prof Hong (Singapore) and benefits from their complementary expertise in ubiquitination and Hippo signaling.

Ubiquitylation regulates cellular processes through modulating stability, function or localisation of proteins. A family of ~100 deubiquitylases (DUBs) remove ubiquitin to reverse these processes. They contribute to multiple signaling pathways and physiological processes, and are associated with cancer (1). Work in the Coulson laboratory has used siRNA library screens to successfully match DUBs with cancer-associated proteins, to determine their roles in signaling and transcription (2,3). Hippo signaling is a highly conserved pathway identified in Drosophila, where mutations result in a “hippopotamus phenotype” through evading apoptosis and promoting proliferation, that is often dysregulated in cancer (4,5). The human Hippo cascade kinases, MST1/2 and LATS1/2, cause YAP/TAZ to shuttle into the nucleus and activate transcription. YAP/TAZ are essential for initiation or growth of most solid tumours. In breast cancer, Wnt signaling reduces ubiquitin-mediated degradation of a YAP/TAZ co-activator (6), however, the role for DUBs in Hippo signaling remains unclear. The Hong/Chan laboratory has long-standing expertise in Hippo signaling and recently identified links between DUBs and core Hippo components. Such DUBs may provide novel therapeutic targets to modulate this pathway in cancer.
The project will use unbiased strategies to profile DUB-Hippo interplay, then establish cellular mechanisms and clinical relevance to specific cancers, by:

1. Systematically identifying DUBs that interact with or modulate Hippo pathway components.
2. Establishing the mechanisms by which selected DUBs regulate Hippo signaling.
3. Demonstrating expression of key DUBs in cancer tissue with dysregulated Hippo signaling.

The student will acquire skills in a broad range of cell biology, molecular biology and molecular pathology techniques. They will spend two years at the Institute of Translational Medicine (ITM, University of Liverpool, UK), and two years at the Institute of Molecular and Cell Biology (IMCB, A*STAR, Singapore). These world-leading research institutes provide state-of the art facilities and stimulating research environments for post-graduate students.

IMCB (www.imcb.a-star.edu.sg/) is an autonomous research institute of the Agency for Science, Technology and Research (A*STAR). Over 30 years IMCB has fostered a vibrant research culture, enabling cutting edge discoveries and nurturing high-quality talent, to catalyze the transformation of Singapore into an international hub for biomedical research. IMCB has trained more than 250 PhD students, recruited more than 800 PhDs from the international community, and published over 2,500 research papers in top international peer-reviewed journals. IMCB has numerous collaborations with industrial, translational, clinical and academic partners both in Singapore and worldwide. The IMCB vision is to remain a premier molecular biology and cell institute with increasing focus on addressing the mechanistic basis of human diseases: cancer cell signaling being one of their 5 major programs in discovery research.
ITM (https://www.liverpool.ac.uk/translational-medicine/) houses the world-class MRC Centre for Drug Safety Science and the MRC Centre for Preclinical Imaging. ITM develops and nurture young talent for careers in academia, and has strong links with the pharmaceutical industry, where more than 100 former graduates hold senior positions. We run a prestigious and long-standing Wellcome Trust 4-year PhD program, and have an excellent track record in training PhD students, who engage with a doctoral training program and vibrant seminar series. Cellular and Molecular Physiology has an established reputation for excellence, hosting internationally recognised researchers with active research programs that are providing new insights into the molecular and cellular processes that underpin pathological diseases. Many faculty are also members of the North West Cancer Research Centre University of Liverpool (https://www.liverpool.ac.uk/nwcrc/).

The studentship will commence on 1st October 2017. Applicants will have a first class or upper second class honours degree (or equivalent) in the biological sciences, and may have additional masters level research experience in cell biology, biochemistry or cancer research.

Formal applications, which should include a cover letter outlining your reasons for applying and a curriculum vitae with the names and contact details of at least two academic referees, should be submitted via email to Mrs Michelle Nelson, [Email Address Removed].
The University of Liverpool is fully committed to promoting gender equality and the Institute of Translational Medicine holds an Athena SWAN Silver Award in recognition of on-going commitment to ensuring these principles are embedded in all its activities and strategic initiatives.

For Informal enquiries, please contact: Prof Judy Coulson, [Email Address Removed]
For Formal applications, please email: Mrs Michelle Nelson, [Email Address Removed]