Open AccessKindlin-2 regulates podocyte adhesion and fibronectin matrix deposition through interactions with phosphoinositides and integrins
Author(s) -
Hong Qu,
Yizeng Tu,
Xiaohua Shi,
Hannu Larjava,
Moin A. Saleem,
Sanford J. Shattil,
Koichi Fukuda,
Jun Qin,
Matthias Kretzler,
Chuanyue Wu
Publication year - 2011
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.076976
Subject(s) - integrin , fibronectin , microbiology and biotechnology , podocyte , biology , focal adhesion , cell adhesion , adhesion , extracellular matrix , signal transduction , chemistry , biochemistry , receptor , cell , kidney , endocrinology , organic chemistry , proteinuria
Kindlin-2 is a FERM and PH domain-containing integrin-binding protein that is emerging as an important regulator of integrin activation. How kindlin-2 functions in integrin activation, however, is not known. We report here that kindlin-2 interacts with multiple phosphoinositides, preferentially with phosphatidylinositol 3,4,5-trisphosphate. Although integrin-binding is essential for focal adhesion localization of kindlin-2, phosphoinositide-binding is not required for this process. Using biologically and clinically relevant glomerular podocytes as a model system, we show that integrin activation and dependent processes are tightly regulated by kindlin-2: depletion of kindlin-2 reduced integrin activation, matrix adhesion and fibronectin matrix deposition, whereas overexpression of kindlin-2 promoted these processes. Furthermore, we provide evidence showing that kindlin-2 is involved in phosphoinositide-3-kinase-mediated regulation of podocyte-matrix adhesion and fibronectin matrix deposition. Mechanistically, kindlin-2 promotes integrin activation and integrin-dependent processes through interacting with both integrins and phosphoinositides. TGF-β1, a mediator of progressive glomerular failure, markedly increased the level of kindlin-2 and fibronectin matrix deposition, and the latter process was reversed by depletion of kindlin-2. Our results reveal important functions of kindlin-2 in the regulation of podocyte-matrix adhesion and matrix deposition and shed new light on the mechanism whereby kindlin-2 functions in these processes.