TY - JOUR
T1 - The VE-cadherin cytoplasmic domain undergoes proteolytic processing during endocytosis
AU - Su, Wenji
AU - Kowalczyk, Andrew P.
N1 - Funding Information:
We thank Susan Summers for primary cell isolations and members of the Kowalczyk lab for help and advice. We also acknowledge the Emory University Custom Cloning Core Facility for help making the VE-cadherin 691?5 construct. This work was supported by National Institutes of Health Grants RO1AR050501 and RO1AR048266 to A. P. K.
Publisher Copyright:
© 2017 Su and Kowalczyk.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - VE-cadherin trafficking to and from the plasma membrane has emerged as a critical mechanism for regulating cadherin surface levels and adhesion strength. In addition, proteolytic processing of cadherin extracellular and cytoplasmic domains has been reported to regulate cadherin adhesion and signaling. Here we provide evidence that VE-cadherin is cleaved by calpain upon entry into clathrin-enriched domains. This cleavage event occurs between the β-catenin and p120-binding domains within the cadherin cytoplasmic tail. Of interest, VE-cadherin mutants that are resistant to endocytosis are similarly resistant to cleavage. Furthermore, p120-catenin overexpression blocks cadherin internalization and cleavage, coupling entry into the endocytic pathway with proteolytic processing. Of importance, the cleavage of the VE-cadherin tail alters the postendocytic trafficking itinerary of the cadherin, resulting in a higher turnover rate due to decreased recycling and increased degradation. In conclusion, this study identifies a novel proteolytic event that regulates the trafficking of VE-cadherin after endocytosis.
AB - VE-cadherin trafficking to and from the plasma membrane has emerged as a critical mechanism for regulating cadherin surface levels and adhesion strength. In addition, proteolytic processing of cadherin extracellular and cytoplasmic domains has been reported to regulate cadherin adhesion and signaling. Here we provide evidence that VE-cadherin is cleaved by calpain upon entry into clathrin-enriched domains. This cleavage event occurs between the β-catenin and p120-binding domains within the cadherin cytoplasmic tail. Of interest, VE-cadherin mutants that are resistant to endocytosis are similarly resistant to cleavage. Furthermore, p120-catenin overexpression blocks cadherin internalization and cleavage, coupling entry into the endocytic pathway with proteolytic processing. Of importance, the cleavage of the VE-cadherin tail alters the postendocytic trafficking itinerary of the cadherin, resulting in a higher turnover rate due to decreased recycling and increased degradation. In conclusion, this study identifies a novel proteolytic event that regulates the trafficking of VE-cadherin after endocytosis.
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U2 - 10.1091/mbc.E16-09-0658
DO - 10.1091/mbc.E16-09-0658
M3 - Article
C2 - 27798242
AN - SCOPUS:85008192137
VL - 28
SP - 76
EP - 84
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
SN - 1059-1524
IS - 1
ER -