Gab2 (Grb2-Associated Binder2) Plays a Crucial Role in Inflammatory Signaling and Endothelial Dysfunction

Abstract

Objective: In response to inflammatory insult, endothelial cells express cell adhesion molecules and TF (tissue factor), leading to increased adhesion of leukocytes to the endothelium and activation of coagulation. Enhanced coagulation could further exacerbate inflammation. Identifying key signaling molecule(s) that drive both inflammation and coagulation may help devise effective therapeutic strategies to treat inflammatory and thrombotic disorders. The aim of the current study to determine the role of Gab2 (Grb2-associated binder2), which is known to play a crucial role in the signaling evoked by growth factors and antigen receptors, in inflammatory signaling pathways and contributing to vascular dysfunction. Approach and Results: WT (wild type) and Gab2-silenced endothelial cells were treated with TNFα (tumor necrosis factor alpha), IL (interleukin)-1β, or lipopolysaccharide (LPS). Activation of key signaling proteins in the inflammatory signaling pathways and expression of cell adhesion molecules, TF, and inflammatory cytokines were analyzed. Gab2 −/ − and WT littermate mice were challenged with LPS or S pneumoniae , and parameters of inflammation and activation of coagulation were assessed. Gab2 silencing in endothelial cells markedly attenuated TNFα-induced, IL-1β–induced, and LPS-induced expression of TF, cell adhesion molecules, and inflammatory cytokines/chemokines. Gab2 silencing suppressed TNFα-induced, IL-1β–induced, and LPS-induced phosphorylation and ubiquitination of TAK1 and activation of MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor kappa B). Immunoprecipitation studies revealed that the Src kinase Fyn phosphorylates Gab2. Gab2 −/− mice are protected from LPS or S pneumoniae –induced vascular permeability, neutrophil infiltration, thrombin generation, NET formation, cytokine production, and lung injury. Conclusions: Our studies identify, for the first time, that Gab2 integrates signaling from multiple inflammatory receptors and regulates vascular inflammation and thrombosis.

Periodontitis and cardiometabolic disorders: The role of lipopolysaccharide and endotoxemia

“…In atherosclerotic lesions, macrophages and endothelial cells in particular express toll‐like receptor 2 and toll‐like receptor 4 receptors, and toll‐like receptor 4 expression in macrophages is upregulated by oxidized low‐density lipoprotein 123,124 . Lipopolysaccharide may activate endothelial cells and induce the expression of cytokines and chemokines, tissue factor, and cell adhesion molecules, leading to increased adhesion of leukocytes to the endothelium and increased vascular permeability 125‐128 . The vascular inflammation activates coagulation and may lead to thrombosis 129 .…”

“…123,124 Lipopolysaccharide may activate endothelial cells and induce the expression of cytokines and chemokines, tissue factor, and cell adhesion molecules, leading to increased adhesion of leukocytes to the endothelium and increased vascular permeability. [125][126][127][128] The vascular inflammation activates coagulation and may lead to thrombosis. 129 (Continues) cells within atherosclerotic plaques, lipopolysaccharide may contribute to atherosclerotic damage via cytokine and prostaglandin induction and oxidative stress.…”

A multi-phenotype analysis reveals 19 susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma

“…FAP, CDKL1, MARK3, RAB11FIP2, GAB2, SUOX and SOX6 . Although some genetic variants within these genes have pleiotropic effects with pigmentation traits, the aforementioned genes have established roles in cancer cell proliferation, migration and invasion, and downregulation of apoptosis in melanoma, colorectal cancer and breast cancer 45 – 51 . Some of these loci are potential drug targets.…”

A multi-phenotype analysis reveals 19 novel susceptibility loci for basal cell carcinoma and 15 for squamous cell carcinoma

“…Although loci within these genes had pleiotropic effects with pigmentation traits, the aforementioned genes have established roles in tumor cell proliferation, migration and invasion, and downregulation of apoptosis in a number of cancers e.g. melanoma, colorectal cancer, and breast cancer 39, 48–50,74,75,113 . Besides the novel findings, our results further emphasise the shared biology between cutaneous melanoma and keratinocyte cancers.…”

“…Following inflammatory stimuli (e.g. by cytokines) GAB2 is required in inflammatory signalling during tumorigenesis 39,40 . It enhances cancer cell proliferation e.g.…”