Crosstalk between PAK1 signalling and intracellular trafficking

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Epithelial cells are an important component of many different tissues and organs in the body. They form a sheet of highly adherent cells that line all inside our internal organs and externally to form our skin. Epithelial cells are an essential cell type for life, and alterations in their structure and function have important clinical implications. As epithelial tissues face many chemicals, biological and environmental challenges, a high proportion of cancers (about 85%) originates in epithelial cells. Dissecting the oncogenic drivers that perturb epithelial cells homeostasis and function will highlight potential therapeutic steps to ameliorate tumour progression.Extensive research has focused on understanding how epithelial cells assemble themselves as tissues and how their function is regulated. A key process that determines tissue structure is the ability of epithelial cells to stick together and strongly. Such orderly organization of epithelial cell-cell adhesion is severely perturbed during tumorigenesis, in inflammatory, chronic and hyper-proliferative diseases. Thus, maintaining cell architecture is important for the function of epithelial tissues.Here we aim to investigate the molecular events that subvert the normal epithelial architecture and disrupt contacts between neighbouring cells. Rac1 and Rabs are two classes of signalling molecules that control distinct cellular processes that are seemingly independent: cell adhesion and intracellular transport. We will study how Rac1 and Rab proteins combine their efforts during tumour progression to promote the removal of adhesion receptors (that glue cells together) from sites where cells contact each other. We find that a Rac1 partner, the kinase PAK1, mediates a seamless integration between these two signalling molecules to integrate their function in space and time to precisely destroy cell-cell contacts. PAK1 gene is amplified or mutated in various cancers, where it is associated with more aggressive tumour phenotypes and poor outcome for patients. It is also activated by different oncogenes such as Rac1 itself or H-Ras, thereby increasing its significance and impact as therapeutics for cancer patients. We find that PAK1 directly modulate the function of a Rab regulator, which in turn can redirect trafficking of adhesion receptors to destroy tissue cohesion and architecture during transformation. Such molecular relationships and outcome will be validated in patient-derived tumour cells that represent the primary tumour status and the corresponding lymph node metastasis in each patient. By understanding the mechanisms via which Rac1 and Rab cross-talk is regulated by PAK1, our work will highlight potential approaches to interfere with tumour progression, by delaying the transition from benign to metastatic tumours.