The Cell-cycle-dependent regulation of adhesion

For most cells in multicellular organisms, cell proliferation is dependent on cell adhesion. During the commitment phase of the cell cycle, sustained adhesion signalling is required to initiate DNA synthesis and suppress apoptosis. During the replication and division phases, major changes in cell shape are obligatory for chromosome segregation and cytokinesis. Understanding the mechanisms that link the cell cycle and cell adhesion will therefore make a major contribution to our understanding of normal cell replication and suggest approaches to intervene in the many prevalent diseases where proliferation is aberrant.

Shape changes during the cell cycle are driven primarily by cytoskeletal rearrangements and modulation of cell adhesion. Across all metazoa, these remodelling events can be so extensive that cells become round and virtually lose their adhesion. The mechanism that triggers the remodelling of adhesion during mitosis is unknown, but we hypothesise a role for the regulatory cell cycle machinery.

In this project, the student will address aspects of the following questions:

• Does the regulatory cell cycle machinery trigger morphological changes prior to mitosis?

• How is adhesion retained in mitotic cells?

• Is the network that controls these processes downstream of a cell cycle checkpoint?

The project will benefit from the complementary knowledge and expertise in the MH (adhesion, mass spectrometry, bioinformatics) and ST labs (cell cycle, imaging). Specifically, building on the existing methodology and workflow established in the MH lab, adhesion complexes will be isolated from adherent, synchronised cells and the peptide and phosphopeptide composition of these complexes will be determined by mass spectrometry. Bioinformatic interrogation of the data will identify protein classes that change, proteins with similar quantitative changes, and potential connections between isolated proteins. Next, potential connections between these proteins will be tested by examining the effects of over-expression or siRNA knockdown on protein recruitment, and followed up by biochemical analyses of signalling pathways or immunocytochemical analyses of protein distribution using expertise in the ST lab. Depending on the candidate, pharmacological inhibition or use of mutants may be further options. In the long-term, the aim will be to develop strategies to manipulate adhesion or mimic its contribution to cell division in order to inform therapeutic strategies.