Cell Signalling Group led by Dr Angeliki Malliri
Tumour initiation and progression result from inappropriate activation of intracellular signalling cascades. Rho-like GTPases are molecular switches in signalling pathways that regulate cytoskeletal and junctional organisation, as well as gene transcription. In this way, Rho proteins influence cell morphology, adhesion, motility, as well as cell cycle progression and cell survival. Rho proteins are transforming in vitro and are essential for Ras-mediated in vitro transformation. Moreover, data has emerged to directly implicate Rho proteins in tumour initiation and progression in vivo.
The Cell Signalling Group focuses on the Rho family GTPase Rac which controls a wide range of cellular processes, including some of those that can become significant at particular stages of tumour development and progression. The present understanding of how specificity in biological output is achieved downstream of Rac is poor. However, this knowledge is crucial for developing therapies that target selective Rac signalling pathways in tumours. Guanine nucleotide exchange factors (GEFs), besides activating Rac, are also considered major determinants of Rac signalling specificity through their roles as molecular scaffolds. The Tiam family of GEFs are selective Rac activators implicated in tumourigenesis. In a previous study, the group demonstrated that mice lacking Tiam1 are resistant to the formation of skin tumours but that when tumours did arise, they were more likely to be malignant. A main interest has therefore been the identification of the cellular processes relevant to neoplasia regulated by Tiam family GEFs. To date, a novel localisation of Tiam1 at centrosomes during early mitosis has been determined, and it has been demonstrated that through Rac Tiam1 regulates centrosome separation during the formation of the mitotic spindle. Furthermore, it has been shown that proper centrosome separation in prophase facilitates subsequent chromosome congression and progression through mitosis, which is required for optimal cell proliferation. The group has also discovered a requirement for the Tiam family member STEF (Tiam2) for optimal tumour cell migration through regulating focal adhesion disassembly by microtubule targeting.
Posttranslational modification of Rac GEFs and Rac itself downstream of extracellular stimuli and/or oncoproteins (proteins that potentially cause tumours) could be another means of influencing the spatio-temporal activity of Rac, as well as selectivity in downstream signalling. Thus, a second focus of the group has been to identify covalent posttranslational modifications (modification of a protein after its synthesis) of both Tiam1 and Rac. Src is a tyrosine kinase oncoprotein that is often overactivated in cancer cells and is able to disrupt cell-cell adhesion resulting in increased cell invasion. The group’s research showed that tyrosine phosphorylation of Tiam1 by Src results in selective depletion of Tiam1 from sites of intercellular contact, disrupting cell-cell adhesions and promoting migration. They also found that Rac1 can be SUMOylated (attachment of a SUMO molecule to a protein) and ubiquitylated (attachment of a ubiquitin molecule to a protein) following growth factor stimulation, mapped the sites of these modifications and showed that they control Rac-GTP levels and are implicated in cell migration.
To gain greater insight into the role of Tiam1 as a molecular scaffold, native protein complexes containing Tiam1 have been purified which allowed the identification of interacting proteins by mass spectrometry. Current investigations focus on the significance of these interactions for the activation and localisation of Tiam1 and for cell-adhesion and migration.
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