Numb controls E-cadherin endocytosis through p120 catenin with aPKC

Cadherin trafficking controls tissue morphogenesis and cell polarity. The endocytic adaptor Numb participates in apicobasal polarity by acting on intercellular adhesions in epithelial cells. However, it remains largely unknown how Numb controls cadherin-based adhesion. Here, we found that Numb direc...

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Bibliographic Details
Published in:Molecular biology of the cell 2011-09, Vol.22 (17), p.3103-3119
Main Authors: Sato, Kazuhide, Watanabe, Takashi, Wang, Shujie, Kakeno, Mai, Matsuzawa, Kenji, Matsui, Toshinori, Yokoi, Keiko, Murase, Kiyoko, Sugiyama, Ikuko, Ozawa, Masayuki, Kaibuchi, Kozo
Format: Article
Language:English
Subjects:
Adaptor Protein Complex alpha Subunits - metabolism
Animals
Cadherins - metabolism
Catenins - metabolism
Cell Adhesion
Cell Line
Cell Polarity
Clathrin - genetics
Clathrin - metabolism
Delta Catenin
Dogs
Endocytosis
Fatty Acid-Binding Proteins - genetics
Fatty Acid-Binding Proteins - metabolism
Gene Knockdown Techniques
Humans
Immunoprecipitation
Membrane Proteins - genetics
Membrane Proteins - metabolism
Microscopy, Fluorescence
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Phosphorylation
Protein Binding
Protein Kinase C - metabolism
Protein Structure, Tertiary
Protein Transport
RNA Interference
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Summary:Cadherin trafficking controls tissue morphogenesis and cell polarity. The endocytic adaptor Numb participates in apicobasal polarity by acting on intercellular adhesions in epithelial cells. However, it remains largely unknown how Numb controls cadherin-based adhesion. Here, we found that Numb directly interacted with p120 catenin (p120), which is known to interact with E-cadherin and prevent its internalization. Numb accumulated at intercellular adhesion sites and the apical membrane in epithelial cells. Depletion of Numb impaired E-cadherin internalization, whereas depletion of p120 accelerated internalization. Expression of the Numb-binding fragment of p120 inhibited E-cadherin internalization in a dominant-negative fashion, indicating that Numb interacts with the E-cadherin/p120 complex and promotes E-cadherin endocytosis. Impairment of Numb induced mislocalization of E-cadherin from the lateral membrane to the apical membrane. Atypical protein kinase C (aPKC), a member of the PAR complex, phosphorylated Numb and inhibited its association with p120 and α-adaptin. Depletion or inhibition of aPKC accelerated E-cadherin internalization. Wild-type Numb restored E-cadherin internalization in the Numb-depleted cells, whereas a phosphomimetic mutant or a mutant with defective α-adaptin-binding ability did not restore the internalization. Thus, we propose that aPKC phosphorylates Numb to prevent its binding to p120 and α-adaptin, thereby attenuating E-cadherin endocytosis to maintain apicobasal polarity.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E11-03-0274