Homophilic Interactions Mediated by Receptor Tyrosine Phosphatases μ and κ. A CRITICAL ROLE FOR THE NOVEL EXTRACELLULAR MAM DOMAIN

Abstract

The receptor-like protein tyrosine phosphatases (RPTP) μ and RPTPκ have a modular ectodomain consisting of four fibronectin type III-like repeats, a single Ig-like domain, and a newly identified N-terminal MAM domain. The function of the latter module, which comprises about 160 amino acids and is found in diverse transmembrane proteins, is not known. We previously reported that both RPTPμ and RPTPκ can mediate homophilic cell interactions when expressed in insect cells. Here we show that despite their striking structural similarity, RPTPμ and RPTPκ fail to interact in a heterophilic manner. To examine the role of the MAM domain in homophilic binding, we expressed a mutant RPTPμ lacking the MAM domain in insect Sf9 cells. Truncated RPTPμ is properly expressed at the cell surface but fails to promote cell-cell adhesion. Homophilic cell adhesion is fully restored in a chimeric RPTPμ molecule containing the MAM domain of RPTPκ. However, this chimeric RPTPμ does not interact with either RPTPμ or RPTPκ. These results indicate that the MAM domain of RPTPμ and RPTPκ is essential for homophilic cell-cell interaction and helps determine the specificity of these interactions. The receptor-like protein tyrosine phosphatases (RPTP) μ and RPTPκ have a modular ectodomain consisting of four fibronectin type III-like repeats, a single Ig-like domain, and a newly identified N-terminal MAM domain. The function of the latter module, which comprises about 160 amino acids and is found in diverse transmembrane proteins, is not known. We previously reported that both RPTPμ and RPTPκ can mediate homophilic cell interactions when expressed in insect cells. Here we show that despite their striking structural similarity, RPTPμ and RPTPκ fail to interact in a heterophilic manner. To examine the role of the MAM domain in homophilic binding, we expressed a mutant RPTPμ lacking the MAM domain in insect Sf9 cells. Truncated RPTPμ is properly expressed at the cell surface but fails to promote cell-cell adhesion. Homophilic cell adhesion is fully restored in a chimeric RPTPμ molecule containing the MAM domain of RPTPκ. However, this chimeric RPTPμ does not interact with either RPTPμ or RPTPκ. These results indicate that the MAM domain of RPTPμ and RPTPκ is essential for homophilic cell-cell interaction and helps determine the specificity of these interactions. Homophilic interactions mediated by receptor tyrosine phosphatases μ and κ. A critical role for the novel extracellular MAM domain.Journal of Biological ChemistryVol. 270Issue 41PreviewVol. 270, p. 14247 Full-Text PDF Open Access