LINGO-1 was originally proposed to function in neurite outgrowth inhibition as an essential component of a cell surface complex responsible for transducing myelin-associated inhibitory factor signaling. Since then, LINGO-1 has been reported to negatively regulate cell surface receptor signaling, differentiation and cell survival pathways associated with mitochondria. Each of these regulates or is known to be regulated by receptor tyrosine kinase (RTK) activity. LINGO-1 is a member of the LIG gene family, members of which are known to modulate RTK function. I tested whether LINGO-1 modulated RTKs.

Evaluating the original proposed model, I performed subcellular localization studies to define the sites of expression endogenous LINGO-1 was associated with. I did not observe LINGO-1 at the cell surface. Instead, LINGO-1 localized to intracellular membranous compartments like late endosome/multivesicular bodies and, surprisingly, mitochondria. I found that components of this proposed original complex displayed subunit competition and that LINGO-1 expression was associated with "co-receptor" degradation. Using LINGO-1 mutations and truncations, I determined LINGO-1 has several structural elements required for localization, interaction and degradation.

LINGO-1 expression is reported to both regulate and be regulated by RTK activity. I found that LINGO-I physically associated with the RTKs TrkA and TrkB. Association was influenced by RTK activity and resulted in Trk degradation. I show that co-receptor degradation occurs via a bafilomycin-sensitive mechanism suggesting degradation is mediated via lysosomes.

LINGO-1 may therefore function as a protein which enhances lysosomal-mediated degradation pathways via direct associations with co-interactor proteins in the endocytic/secretory system to influence cellular phenotypes.