The mannose 6-phosphate binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) interacts with a variety of factors that impinge on tumour invasion and metastasis. It has been shown that expression of wild-type M6P/IGF2R reduces the tumourigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells. We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system. Our results demonstrate that M6P/IGF2R does not require a functional binding site for insulin-like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells. In contrast, simultaneous mutation of both M6P-binding sites is sufficient to impair all cellular functions of the receptor tested. These findings highlight that the interaction between M6P/IGF2R and M6P-modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but also crucial for the ability of the receptor to suppress SCC-VII growth and invasion. Our studies have also revealed that some biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Cell Source Type: research