The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1.
Cell adhesion to the extracellular matrix (ECM) via integrin adhesion receptors initiates signaling cascades leading to changes in cell behavior. While integrin clustering is necessary to initiate cell attachment to the matrix, additional membrane components are necessary to mediate the transmembrane signals and the cell adhesion response that alter downstream cell behavior. Many of these signaling components reside in glycosphingolipid-rich and cholesterol-rich membrane domains such as Tetraspanin Enriched Microdomains (TEMs)/Glycosynapse 3 and Detergent-Resistant Microdomains (DRMs), also known as lipid rafts. In the following article, we will review examples of how components in these membrane microdomains modulate integrin adhesion after initial attachment to the ECM. Additionally, we will present data on a novel adhesion-responsive transmembrane glycoprotein Gp140/CUB Domain Containing Protein 1, which clusters in epithelial cell-cell contacts. Gp140 can then be phosphorylated by Src Family Kinases at tyrosine 734 in response to outside-in signals-possibly through interactions involving the extracellular CUB domains. Data presented here suggests that outside-in signals through Gp140 in cell-cell contacts assemble membrane clusters that associate with membrane microdomains to recruit and activate SFKs. Active SFKs then mediate phosphorylation of Gp140, SFK and PKCdelta with Gp140 acting as a transmembrane scaffold for these kinases. We propose that the clustering of Gp140 and signaling components in membrane microdomains in cell-cell contacts contributes to changes in cell behavior.
Alvares
Stacy M
SM
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Dunn
Clarence A
CA
Brown
Tod A
TA
Wayner
Elizabeth E
EE
Carter
William G
WG
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D000951:Antigens, Neoplasm; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D003902:Detergents / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D047392:beta-Cyclodextrins / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C432044:CDCP1 protein, human; D015815:Cell Adhesion Molecules; D003902:Detergents; D009363:Neoplasm Proteins; D047392:beta-Cyclodextrins; D019061:src-Family Kinases; C031215:betadex