PT  - JOURNAL ARTICLE
AU  - Lukasz Wujak
AU  - Ying Chen
AU  - Klaus T. Preissner
AU  - Malgorzata Wygrecka
TI  - Low density lipoprotein receptor-related protein 1 is a novel activator of β1 Integrin-dependent fibroblast adhesion, spreading and migration
DP  - 2014 Sep 01
TA  - European Respiratory Journal
PG  - P749
VI  - 44
IP  - Suppl 58
4099  - http://erj.ersjournals.com/content/44/Suppl_58/P749.short
4100  - http://erj.ersjournals.com/content/44/Suppl_58/P749.full
SO  - Eur Respir J2014 Sep 01; 44
AB  - Low density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor which mediates clearance of extra cellular matrix components and regulates cell proliferation, migration and adhesion. Based on previous reports demonstrating a pivotal role of LRP1 in the development of fibrotic diseases, we hypothesized that LRP1 function may be impaired in idiopathic pulmonary fibrosis (IPF). PCR and western blot analysis revealed reduced LRP1 expression in lung fibroblasts isolated from IPF patients and bleomycin-challenged mice. Cell migration, adhesion and spreading were markedly decreased in human lung fibroblasts after LRP1 knock-down and in LRP1-deficient mouse embryonic fibroblasts (MEF). Over-expression of truncated LRP1 variant containing second ligand-binding cluster rescued adhesion of LRP-/- MEF. Further investigations showed reduced β1 Integrin endocytosis in LRP-/- MEF indicating that LRP1 promotes β1 Integrin internalization. Analysis of LRP1 and β1 Integrin subcellular distribution revealed that LRP1 and β1 Integrin colocalize in the perincuclear space. GST pull-down and CoIP experiments demonstrated that cytoplasmatic region of LRP1 binds β1 Integrin activator, Kindlin2. Interestingly, over-expression of Kindlin2 rescued cell spreading, filopodia and lamellipodia formation in LRP-/- MEF cells. Collectively, we propose that LRP1 is a novel regulator of β1 Integrin metabolism which acts via Kindlin2 to enhance β1 Integrin endocytosis, thus promoting cell adhesion, spreading and migration. Hence, suppressed LRP1 expression may modulate lung fibroblast behaviour in IPF.