Phosphorylation-independent ubiquitylation and endocytosis of Fc gammaRIIA.
Endocytosis of the Fc receptor Fc gammaRIIA depends on a functional ubiquitin conjugation system, and the receptor becomes ubiquitylated upon ligand binding. Phosphorylation of tyrosines in Fc gammaRIIA by Src family kinases is thought to be the initiating event in its signaling. However, although the Src family kinase inhibitor PP1 inhibited both ligand-induced phosphorylation of Fc gammaRIIA and phagocytosis in ts20 cells expressing Fc gammaRIIA, it did not inhibit receptor ubiquitylation or endocytosis of soluble ligands. Conversely, genistein and the proteasomal inhibitor MG132 did not inhibit receptor phosphorylation but strongly inhibited both receptor ubiquitylation and endocytosis. A region of the receptor lying within the immunoreceptor tyrosine-based activation motif was found to be necessary for both ubiquitylation and endocytosis. Ubiquitylation occurs at the plasma membrane before internalization. Endocytosis of Fc gammaRIIA is dependent on clathrin but independent of the adaptor protein AP-2. These findings point to a novel mechanism for ubiquitylation and endocytosis of this immunoreceptor.
Mero
Patricia
P
Molecular and Cellular Biology Research, Sunnybrook Research Institute, Toronto, Ontario M4N 3M5, Canada.
Zhang
Christine Y
CY
Huang
Zhen-Yu
ZY
Kim
Moo-Kyung
MK
Schreiber
Alan D
AD
Grinstein
Sergio
S
Booth
James W
JW
D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D007976:Leupeptins / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D017452:Receptors, IgG / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D033962:Adaptor Protein Complex 2; D015703:Antigens, CD; D002966:Clathrin; C080568:Fc gamma receptor IIA; D007976:Leupeptins; D061988:Proteasome Inhibitors; D017452:Receptors, IgG; D025801:Ubiquitin; D019061:src-Family Kinases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde