title: SASH1 is a scaffold molecule in endothelial TLR4 signaling.
abstract: Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase β. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation.
authors.affiliation: Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
authors.forename: Shauna M
authors.initials: SM
authors.lastname: Dauphinee
authors.forename: Ashley
authors.initials: A
authors.lastname: Clayton
authors.forename: Angela
authors.initials: A
authors.lastname: Hussainkhel
authors.forename: Cindy
authors.initials: C
authors.lastname: Yang
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Park
authors.forename: Megan E
authors.initials: ME
authors.lastname: Fuller
authors.forename: Josip
authors.initials: J
authors.lastname: Blonder
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D000818:Animals; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D051550:I-kappa B Kinase / Q000378:metabolism; D007113:Immunity, Innate; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C505822:Sash1 protein, mouse; C493487:Tlr4 protein, mouse; C496564:Chuk protein, mouse