Numb Induces E-Cadherin Adhesion Dissolution, Cytoskeleton Reorganization, and Migration in Tubular Epithelial Cells Contributing to Renal Fibrosis

被引：15

作者：

Ding, X. ^{[1
]}

Ma, M. ^{[2
]}

Teng, J. ^{[1
]}

Shao, F. ^{[4
]}

Teng, R. K. F. ^{[5
]}

Zhou, S. ^{[3
]}

Zhang, Y. ^{[3
]}

Wu, E. ^{[3
]}

Wang, X. ^{[1
,3
]}

机构：

[1] Zhengzhou Univ, Affiliated Hosp 1, Dept Neurol, Zhengzhou 450052, Peoples R China

[2] Zhengzhou Univ, Peoples Hosp, Dept Neurol, Zhengzhou 450052, Peoples R China

[3] N Dakota State Univ, Coll Pharm Nursing & Allied Sci, Dept Pharmaceut Sci, Fargo, ND 58105 USA

[4] Zhengzhou Univ, Peoples Hosp, Dept Nephrol, Zhengzhou 450052, Peoples R China

[5] Shenzhen Univ, Coll Informat & Engn, Shenzhen, Peoples R China

来源：

CURRENT MOLECULAR MEDICINE | 2015年 / 15卷 / 04期

基金：

中国国家自然科学基金;

关键词：

E-cadherin; EMT; migration; NRK52E; Numb; renal fibrosis; TO-MESENCHYMAL TRANSITION; TGF-BETA; RHO-GTPASES; EXPRESSION; PROTEIN; ENDOCYTOSIS; IDENTIFICATION; INTEGRINS; DIVISION;

D O I：

10.2174/1566524015666150505162015

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Numb, an endocytic protein, is involved in both neural differentiation and protein post-endocytic trafficking. Although negative Numb expression has been linked to human mammary carcinomas, little is known about its expression and functions in other diseases. In the present study, we observed that Numb is expressed in renal tubule epithelia and its expression is increased in the fibrotic kidney in vivo. We determined that in proximal tubular epithelial cells (NRK52E cells), TGF-beta 1 induces the expression of Numb and ectopic expression of Numb leads to dissolution of E-cadherin adhesion, reorganization of cytoskeleton, activation of Rac1 and Cdc42, and enhancement of migration. Either knockdown of alpha-adaptin or overexpression of Numb asparagine-proline-phenylalanine (NPF) mutant interferes with AP-2 dependent endocytosis and rescues E-cadherin level in NRK52E cells. Moreover, knockdown of integrin beta 1 or alpha-adaptin, and overexpression of a Numb dominant-negative form (Numb phosphotyrosine binding [PTB] domain) impair integrin endocytosis, and markedly inhibit Numb-induced cell migration and activation of Rac1 and Cdc42. Taken together, our work identifies Numb as an important player in renal fibrosis, by regulating epithelial-to-mesenchymal transition (EMT) process including E-cadherin adhesion dissolution, actin reorganization, and migration enhancement in NRK52E cells.

引用

页码：368 / 379

页数：12

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