Generation of E-cadherin fragments and their functions. A, cleavage of the full-length E-cadherin by α-secretase, γ-secretase, and caspase-3 generates the sE-cad and E-cad/CTF1, E-cad/CTF2, and E-cad/CTF3 fragments, respectively. B, oncogenic functions of the sE-cad and E-cad/CTF2 fragments. Generation of sE-cad by E-cadherin cleavage reduces the amount of full-length E-cadherin on the plasma membrane (1), disrupts existing adherens junctions (2), activates the expression of MMPs to augment ectodomain shedding (3), and activates EGFR pathway signaling by different mechanisms (4). Intracellular cleavage of E-cadherin activates Wnt/β-catenin pathway signaling (5). CD, cytoplasmic domain; TM, transmembrane domain.