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TGFBI remodels adipose metabolism by regulating the Notch-1 signaling pathway
Lee Seul Gi,Chae Jongbeom,Woo Seon Min,Seo Seung Un,Kim Ha-Jeong,Kim Sang-Yeob,Schlaepfer David D.,Kim In-San,Park Hee-Sae,Kwon Taeg Kyu,Nam Ju-Ock 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-
Extracellular matrix proteins are associated with metabolically healthy adipose tissue and regulate inflammation, fibrosis, angiogenesis, and subsequent metabolic deterioration. In this study, we demonstrated that transforming growth factor-beta (TGFBI), an extracellular matrix (ECM) component, plays an important role in adipose metabolism and browning during high-fat diet-induced obesity. TGFBI KO mice were resistant to adipose tissue hypertrophy, liver steatosis, and insulin resistance. Furthermore, adipose tissue from TGFBI KO mice contained a large population of CD11b+ and CD206+ M2 macrophages, which possibly control adipokine secretion through paracrine mechanisms. Mechanistically, we showed that inhibiting TGFBI-stimulated release of adipsin by Notch-1-dependent signaling resulted in adipocyte browning. TGFBI was physiologically bound to Notch-1 and stimulated its activation in adipocytes. Our findings revealed a novel protective effect of TGFBI deficiency in obesity that is realized via the activation of the Notch-1 signaling pathway.
VEGF-Induced Vascular Permeability Is Mediated by FAK
Chen, X.,Nam, J.O.,Jean, C.,Lawson, C.,Walsh, Colin T.,Goka, E.,Lim, S.T.,Tomar, A.,Tancioni, I.,Uryu, S.,Guan, J.L.,Acevedo, Lisette M.,Weis, Sara M.,Cheresh, David A.,Schlaepfer, David D. Cell Press 2012 DEVELOPMENTAL CELL Vol.22 No.1
Endothelial cells (ECs) form cell-cell adhesive junctional structures maintaining vascular integrity. This barrier is dynamically regulated by vascular endothelial growth factor (VEGF) receptor signaling. We created an inducible knockin mouse model to study the contribution of the integrin-associated focal adhesion tyrosine kinase (FAK) signaling on vascular function. Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation, rapid FAK localization to cell-cell junctions, binding of the FAK FERM domain to the vascular endothelial cadherin (VE-cadherin) cytoplasmic tail, and direct FAK phosphorylation of β-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-β-catenin dissociation and EC junctional breakdown. Kinase inhibited FAK is in a closed conformation that prevents VE-cadherin association and limits VEGF-stimulated β-catenin Y142 phosphorylation. Our studies establish a role for FAK as an essential signaling switch within ECs regulating adherens junction dynamics.