CDHR5 splice isoform cooperation promotes apical targeting of the brush border cadherin

Cadherin-related family member 5 (CDHR5) is an adhesion molecule that is highly enriched in the microvilli found on the surface of transporting epithelial cells of the gut and kidney. CDHR5 localizes to the distal tips of these microvilli as part of an adhesion complex that drives assembly of microvilli into a cohesive apical brush border, a hallmark feature of polarized transporting epithelial cells. Loss of CDHR5 correlates with poor prognosis of colon cancer patients, while forced over-expression of CDHR5 in colorectal cancer cell lines blocks their ability to form tumors in mice. Despite acting as an apparent tumor suppressor, how CDHR5 targets to the apical domain of transporting epithelial cells to exert its tumor suppressor effects is poorly understood. Here, we show that CDHR5 is expressed as three dominant splice isoforms in intestinal epithelial cells that differ only in the presence and composition of a membrane-proximal extracellular mucin-like domain. When present in the CDHR5 ectodomain, this mucin-like domain restricted targeting of the cadherin to apical microvilli. Importantly, we show that this restriction could be bypassed through apparent hetero-oligomer formation between the splice isoforms that have the mucin-like domain and the isoform that does not.