Tetraspanin CD151 Promotes Cell Migration by Regulating Integrin Trafficking

Li Liu,Bo He,Wei M Liu,Dongming Zhou,John V Cox,Xin A Zhang

doi:10.1074/jbc.m701165200

Li Liu, Bo He + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m701165200

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Abstract

Regulation of cell migration is an important feature of tetraspanin CD151. Although it is well established that CD151 physically associates with integrins, the mechanism by which CD151 regulates integrin-dependent cell migration is basically unknown. Given the fact that CD151 is localized in both the plasma membrane and intracellular vesicles, we found that CD151 and its associated alpha3beta1, alpha5beta1, and alpha6beta1 integrins undergo endocytosis and accumulate in the same intracellular vesicular compartments. CD151 contains a YRSL sequence, a YXXvarphi type of endocytosis/sorting motif, in its C-terminal cytoplasmic domain. Mutation of this motif markedly attenuated CD151 internalization. The loss of CD151 trafficking completely abrogated CD151-promoted cell migration on extracellular matrices such as laminin and diminished the internalization of its associated integrins, indicating a critical role for integrin trafficking in regulating cell motility. In conclusion, the YXXvarphi motif-mediated internalization of CD151 promotes integrin-dependent cell migration by modulating the endocytosis and/or vesicular trafficking of its associated integrins.

Highlights

Is similar to the distribution of LN-binding integrins such as ␣3␤1, ␣6␤1, ␣6␤4, and ␣7␤1 [13], which is consistent with its ability to associate with these integrins and with a likely concomitant function during development [14, 15]
The Tyr and Leu residues in CD151 YRSL motif were replaced with alanine residues simultaneously, and the resulting YRSL 3 ARSA mutant was designated as the Yala mutant
The blotting of CD151 immunoprecipitates with CD151 monoclonal antibodies (mAb) ensured that the biotinylated ϳ30-kDa band in CD151 immunoprecipitate is CD151 (Fig. 3A, bottom panel). These results indicate that the Yala mutation did not alter the association of CD151 with cell surface integrins and that CD151 endocytosis is not required for CD151-integrin complex formation

Summary

Introduction

Is similar to the distribution of LN-binding integrins such as ␣3␤1, ␣6␤1, ␣6␤4, and ␣7␤1 [13], which is consistent with its ability to associate with these integrins and with a likely concomitant function during development [14, 15]. The deletion or exchange of the CD151 C-terminal cytoplasmic tail markedly impaired integrin ␣6␤1-dependent cell spreading and cellular morphogenesis [5, 18]. The YXX␾ motifs in the cytoplasmic domain of transmembrane proteins are recognized by adaptor protein-2 complex, a core component of clathrin endocytic machinery [26, 27]. This led us to hypothesize that the YRSL motif drives CD151 endocytosis, is responsible for the func-. CD151 Endocytosis Regulates Cell Migration tional importance of CD151 C-terminal cytoplasmic domain, and regulates CD151 activities such as integrin-dependent cell movement

Methods

Results

Conclusion