Rac and PAK: a partnership at the interface between junction disassembly and increased cell motility

Tight adhesion between neighbouring cells plays an important role in the maintenance of tissue cohesion and architecture. During tumorigenesis, disruption of cell-cell adhesion is a key event for cell detachment from solid tumours and metastasis. We found that increased activity of Rac, a signalling protein, leads to a rapid destabilization of cell-cell contacts and increased migration and invasion of cells. Similar Rac hyper-activity is found in many different types of tumours and participate in malignant transformation. Here we propose to identify regulatory molecules that are recruited by Rac to help perturb cell-cell contact stability and investigate their potential as therapeutic targets during tumorigenesis.

A major focus of research in cancer cell biology is to identify the regulatory mechanisms of the conversion of adherent cells in solid tumours into de-differentiated, highly invasive tumour cells. In many different tumour types there is a strong correlation between loss cadherin-dependent cell-cell contacts of cell-cell and increased metastatic potential.

We found that inappropriate Rac activation can disrupt cell-cell adhesion by inducing internalization and degradation of cadherins. Inappropriate activation of the small GTPase Rac is found in a broad range of tumours and result from different mechanisms commonly found in cancers. The mechanism via which Rac can perturb cell-cell contacts is not known. Interestingly, our recent results show that disruption of junctions by Rac can be reversed by inhibition of its target PAK and Rab11, a small GTPase that regulates early endocytic trafficking. This data is exciting in the context of tumour metastasis as Rac, PAK endocytic trafficking are also key players in cell motility. Consistent with our data, Rac and PAK have been implicated in increased motility and invasiveness of tumour cells. Thus the pathway identified in our study may participate in the coordination of junction destabilization and increased motility observed during metastasis.

The interplay between Rac, PAK and Rab11 is novel and significant to tumour progression. Here we will investigate the mechanisms required for junction disassembly and identify the:
1. Molecular mechanisms of destabilization of cadherin complexes by Rac and PAK;
2. Cellular processes by which Rac, PAK and Rab11 interfere with cell-cell contact stability;
3. Molecular mechanisms downstream of Rac and PAK that modulate Rab11 function.

This proposal will provide considerable insights into the intracellular mechanisms that lead to cadherin destabilization from junctions following Rac activation. Using biochemical and cell biology approaches, we expect to unravel a potential strategy to minimize cell detachment and de-differentiation during tumorigenesis.