39.5: Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB. Similarly, Ephrin is also classified into two types — EphrinA and EphrinB. EphrinA ligands are attached to the plasma membrane through glycosylphosphatidylinositol (GPI), and EphrinB has a transmembrane domain with a cytoplasmic tail. When Ephrin binds to Eph, bidirectional signaling is activated. A forward signal in Eph cells and a reverse signal in Ephrin cells.
As the intestinal cells continuously renew themselves, the Ephrin-Eph signal plays an important role in properly segregating cells and thereby maintaining the intestinal architecture. The Wnt signal triggers EphB2 expression in intestinal stem cells (ISCs) and EphB3 expression in Paneth cells. Mutations in EphB3 can cause misplacement of Paneth cells. In one study with EphB3 mutant mice, the Paneth cells migrated to the villi instead of the crypts’ base.
EphB is a tumor suppressor, and loss of this receptor leads to intestinal tumors. During wound repair, Eph receptor and Ephrin ligands are upregulated in the wounded cells. The resultant cell signaling causes cleavage of adherens junctions between the cells, allowing them to migrate to the wound and help in the healing process.
