title: μ2-Dependent endocytosis of N-cadherin is regulated by β-catenin to facilitate neurite outgrowth.
abstract: Circuit formation in the brain requires neurite outgrowth throughout development to establish synaptic contacts with target cells. Active endocytosis of several adhesion molecules facilitates the dynamic exchange of these molecules at the surface and promotes neurite outgrowth in developing neurons. The endocytosis of N-cadherin, a calcium-dependent adhesion molecule, has been implicated in the regulation of neurite outgrowth, but the mechanism remains unclear. Here, we identified that a fraction of N-cadherin internalizes through clathrin-mediated endocytosis (CME). Two tyrosine-based motifs in the cytoplasmic domain of N-cadherin recognized by the μ2 subunit of the AP-2 adaptor complex are responsible for CME of N-cadherin. Moreover, β-catenin, a core component of the N-cadherin adhesion complex, inhibits N-cadherin endocytosis by masking the 2 tyrosine-based motifs. Removal of β-catenin facilitates μ2 binding to N-cadherin, thereby increasing clathrin-mediated N-cadherin endocytosis and neurite outgrowth without affecting the steady-state level of surface N-cadherin. These results identify and characterize the mechanism controlling N-cadherin endocytosis through β-catenin-regulated μ2 binding to modulate neurite outgrowth.
authors.affiliation: Taiwan International Graduate Program, Molecular and Cellular Biology Program, Academia Sinica, Taiwan, Republic of China.|Institute of Molecular Biology, Academia Sinica, Taiwan, Republic of China.|Graduate Institute of Life Sciences, National Defense Medical Center, Taiwan, Republic of China.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Taiwan International Graduate Program, Molecular and Cellular Biology Program, Academia Sinica, Taiwan, Republic of China.|Institute of Molecular Biology, Academia Sinica, Taiwan, Republic of China.|Development Center for Biotechnology, Institute of Pharmaceutics, Taiwan, Republic of China.
authors.forename: Chin-Yin
authors.initials: CY
authors.lastname: Tai
mesh_terms: D033983:Adaptor Protein Complex mu Subunits / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002522:Chlorocebus aethiops; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D000071446:Neuronal Outgrowth / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D033983:Adaptor Protein Complex mu Subunits; D015820:Cadherins; D015815:Cell Adhesion Molecules; D002966:Clathrin; D051176:beta Catenin; D014443:Tyrosine; C026741:2-tyrosine
keywords: 
  AP-2 adaptor complex; N-cadherin; cell adhesion; endocytosis; β-catenin; μ2 subunit