Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

The Coxsackie and adenovirus receptor (CAR) is a member of the immunoglobulin superfamily of adhesion molecules. As its name implies, it was first identified as the high affinity receptor for adenovirus type 5, the most commonly used adenoviral vector for gene transfer. My laboratory's interest in CAR stems from the fact that we routinely use adenovirus (Ad) vectors for gene transfer to muscle, nervous system and tumour cells. As such we have been interested in determining the expression pattern of CAR and means of modulating its expression. In the process, we have started studying the multiple functions of CAR in these tissues.
CAR expression is regulated developmentally and in a tissue-specific manner. Ectopic over expression studies in vitro indicate that the extracellular domain of CAR can mediate homotypic cell-cell adhesion. Accordingly CAR is localized to tight and adherens junctions in polarized epithelia. Highest levels of CAR expression are observed in prenatal and neonatal tissues. This pattern of expression suggests CAR could play a role in the growth, migration or differentiation of embryonic or neonatal tissues. Such a role for CAR is further supported by the observation of loss of CAR expression in several types of cancer. We were the first to show that the highly conserved cytoplasmic domain of CAR was essential for regulating cell migration. Through pulldown assays and proteomic analysis we have identified several binding partners, among which were the cytoskeletal proteins tubulin and actin, binding directly to CAR. We have also shown that CAR is processed by metalloproteases, specifically ADAM10, leading to shedding of its extracellular domain. This is followed by cleavage through the gamma-secretase complex to produce an intracellular cytoplasmic fragment, thus generating potentially important signalling molecules.
Our long term objective is to understand how an adhesion molecule such as CAR transmits extracellular cues into intracellular signals. In the past few years we have concentrated on two biological systems, tumour cells and neurons. In both cell types, CAR plays crucial roles in cell migration. In tumour cells, CAR expression leads to inhibition of migration and invasion while in neurons, CAR expression promotes process extension (neurite outgrowth).
Our specific aims are to:
1) determine the functional relevance of the processing of CAR
2) determine whether CAR's intracellular cytoplasmic domain plays a signaling role
3) study the function of CAR in the developing nervous system