Class A scavenger receptor-mediated cell adhesion requires the sequential activation of Lyn and PI3-kinase.
Class A scavenger receptors (SR-A) participate in multiple macrophage functions including macrophage adhesion to modified proteins. SR-A-mediated adhesion may therefore contribute to chronic inflammation by promoting macrophage accumulation at sites of protein modification. The mechanisms that couple SR-A binding to modified proteins with increased cell adhesion have not been defined. In this study, SR-A expressing HEK cells and SR-A+/+ or SR-A-/- macrophages were used to delineate the signaling pathways required for SR-A-mediated adhesion to modified protein. Inhibiting G(i/o) activation, which decreases initial SR-A-mediated cell attachment, did not prevent the subsequent spreading of attached cells. In contrast, inhibition of Src kinases or PI3-kinase abolished SR-A-dependent cell spreading without affecting SR-A-mediated cell attachment. Consistent with these results, the Src kinase Lyn and PI3-kinase were sequentially activated during SR-A-mediated cell spreading. Furthermore, activation of both Lyn and PI3-kinase was required for enhancing paxillin phosphorylation. Activation of a Src kinase-PI3-kinase-Akt pathway was also observed in cells expressing a truncated SR-A protein that does not internalize indicating that SR-A-mediated activation of intracellular signaling cascades following adhesion to MDA-BSA is independent of receptor internalization. Thus SR-A binding to modified protein activates signaling cascades that have distinct roles in regulating initial cell attachment and subsequent cell spreading.
Nikolic
Dejan M
DM
Department of Molecular and Biomedical Pharmacology, The University of Kentucky, Lexington, KY 40536, USA.
Cholewa
Jill
J
Gass
Cecelia
C
Gong
Ming C
MC
Post
Steven R
SR
D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D048430:Cell Shape; D004789:Enzyme Activation; D006801:Humans; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008315:Malondialdehyde / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000502:physiology*; D012710:Serum Albumin, Bovine / Q000737:chemistry; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
D051117:Scavenger Receptors, Class A; D012710:Serum Albumin, Bovine; D008315:Malondialdehyde; D019869:Phosphatidylinositol 3-Kinases; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases