Phosphoinositide 3-kinase is activated by MUC1 but not responsible for MUC1-induced suppression of Toll-like receptor 5 signaling.
MUC1 is a membrane-tethered mucin-like glycoprotein expressed on the surface of various mucosal epithelial cells as well as hematopoietic cells. Recently, we showed that MUC1 suppresses flagellin-induced Toll-like receptor (TLR) 5 signaling both in vivo and in vitro through cross talk with TLR5. In this study, we determined whether phosphoinositide 3-kinase (PI3K), a negative regulator of TLR5 signaling, is involved in the cross talk between MUC1 and TLR5 using various genetically modified epithelial cell lines. Our results showed 1) activation of MUC1 induced recruitment of the PI3K regulatory subunit p85 to the MUC1 cytoplasmic tail (CT) as well as Akt phosphorylation, 2) MUC1-induced Akt phosphorylation required the presence of Tyr(20) within the PI3K binding motif of the MUC1 CT, and 3) mutation of Tyr(20) or pharmacological inhibition of PI3K activation failed to block MUC1-induced suppression of TLR5 signaling. We conclude that whereas PI3K is downstream of MUC1 activation and negatively regulates TLR5 signaling, it is not responsible for MUC1-induced suppression of TLR5 signaling.
Kato
Kosuke
K
Immunology and Asthma Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108-5127, USA.
Lu
Wenju
W
Kai
Hirofumi
H
Kim
K Chul
KC
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016827:CD8 Antigens / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D009077:Mucins / Q000737:chemistry / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051198:Toll-Like Receptor 5 / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D016827:CD8 Antigens; D009077:Mucins; D051198:Toll-Like Receptor 5; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt