title: Kindlin-2 regulates podocyte adhesion and fibronectin matrix deposition through interactions with phosphoinositides and integrins.
abstract: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Qu
authors.forename: Yizeng
authors.initials: Y
authors.lastname: Tu
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Shi
authors.forename: Hannu
authors.initials: H
authors.lastname: Larjava
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Sanford J
authors.initials: SJ
authors.lastname: Shattil
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
mesh_terms: D002448:Cell Adhesion; D002460:Cell Line; D005109:Extracellular Matrix / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D050199:Podocytes / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C477322:FERMT3 protein, human; D005353:Fibronectins; D019012:Integrin beta1; D039661:Integrin beta3; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010716:Phosphatidylinositols; D053773:Transforming Growth Factor beta1