Endocytosis as a Regulator of Cell Signalling
Figure 1: the endocytic pathway
Figure 2: schematic representation of border cell migration
Endocytosis and Collective Cell Migration
Collective cell migration is important during development and wound healing. However, undesired migration takes place during the formation of metastasis in cancer. These migrations are due to group of cells. Hence it is of high importance to understand the molecular mechanism regulating collective cell migration in order to uncover new potential targets to block metastasis formation. We use border cell migration in the Drosophila egg chamber as a model of collective cell migration (Fig. 2). Border cell migration resembles metastasis formation by several aspects: the cells migrate collectively through the action of ligands to Receptor Tyrosine Kinases (RTKs), they invade a tissue and they home when they reach their final destination. We recently showed that the small GTPases Rab5 and Rab11 and the exocyst complex (see Fig.1 and Assaker et al., PNAS 2010) are involved in border cell migration by maintaining the polarization of the activity of RTKs. We are further investigating how the Rab proteins are regulated in this process (see below) and what is the exact molecular mechanism regulated by them. In particular, we want to understand how endocytosis might regulate the collective behavior of border cell and the activity of Rho GTPases, which are necessary to provide the driving force during border cell migration. Furthermore, we want to determine if our observations are specific for border cell migration or conserved in other type of collective cell migration in Drosophila (trachea formation) or in cell culture.
Endocytosis and Notch Signalling
Notch signalling is a complex cell signalling event requiring both the endocytosis of the receptor Notch and of the ligand Delta (Fig.3). Notch is overactivated when the receptor is blocked in the endocytic pathway. Our goal is to identify in which compartments this activation can take place. Furthermore the mechanism of Notch ativation is context-dependent. We want to identify what mechanism overactivates Notch in different tissues. At the same time, we want to identify the molecular mechanism acting on the Notch ligand Delta. For these projects, we are combining in vivo experiments in Drosophila with cell culture approaches.
Figure 3: Role of endocytosis in the regulation of Notch signalling
Figure 4: The Rab cycle
Regulation of Endocytic Rab Proteins
Small GTPases are key regulators of vesicular trafficking by acting as on/off switches for specific transport steps. GTPase activating proteins (GAPs) and Guanine Exchange Factors (GEFs) are key regulators of Rab proteins (Fig.4). GAP proteins are easily identifiable since they contain a so called TBC domain. Interestingly there are 27 potential GAP proteins in Drosophila for 33 Rab proteins, suggesting that there is a specific GAP for, more or less, each Rab protein. By combining in vivo, cell culture and in vitro experiments, we have recently identified Evi5 as the GAP protein acting on Rab11 during border cell migration (Laflamme et al., JCB 2012). However our data also suggest that other GAP might act on Rab11 in other tissue. Here we want to answer these questions: is Evi5 the unique Rab11 GAP, is there really a 1:1 Rab/GAP distribution, is the specificity of GAP protein influence by post-translational modification. In addition, we would like to identify the GEF protein(s) acting on Rab11 and on other Rabs.
|Last modified: August 14, 2012|