Metalloproteinase-mediated release of the ectodomain of L1 adhesion molecule

The L1 adhesion molecule is an approx. 200-220 kDa type I membrane glycopro tein belonging to the immunoglobulin (Ig) superfamily.. L1 can bind in a ho motypic fashion and was shown to support integrin-mediated binding via RGDs in the 6th Ig-like domain. In addition to its cell-surface expression, L1 can occur in the extracellular matrix (ECM). Here we demonstrate that L1 is constitutively released from the cell surface by membrane-proximal cleavag e. L1 shed from B16F10 melanoma cells remains intact and can serve as subst rate for integrin-mediated cell adhesion and migration. The release of L1 o ccurs in mouse and human cells and is blocked by the metalloproteinase inhi bitor TAPI (Immunex compound 3). This compound has been shown previously to block release of L-selectin and TNF-alpha which is mediated by the membran e-bound metalloproteinase TNF-alpha converting enzyme (TACE). Using CHO cel ls that are low in TACE expression and do not release L-selectin we demonst rate that L1 release is distinct from L-selectin shedding. We propose that cell-surface release may be necessary for the conversion of L1 from a membr ane into an ECM protein.