The CY domain of the Fcgamma RIa alpha-chain (CD64) alters gamma-chain tyrosine-based signaling and phagocytosis.
Although the cytoplasmic domain of the human FcgammaRIa alpha-chain lacks tyrosine-based phosphorylation motifs, it modulates receptor cycling and receptor-specific cytokine production. The cytoplasmic domain of FcgammaRIa is constitutively phosphorylated, and the inhibition of dephosphorylation with okadaic acid, an inhibitor of type 1 and type 2A protein serine/threonine phosphatase, inhibits both receptor-induced activation of the early tyrosine phosphorylation cascade and receptor-specific phagocytosis. To explore the basis for these effects of the cytoplasmic domain of FcgammaRIa, we developed a series of human FcgammaRIa molecular variants, expressed in the murine macrophage cell line P388D1, and demonstrate that serine phosphorylation of the cytoplasmic domain is an important regulatory mechanism. Truncation of the cytoplasmic domain and mutation of the cytoplasmic domain serine residues to alanine abolish the okadaic acid inhibition of phagocytic function. In contrast, the serine mutants did not recapitulate the selective effects of cytoplasmic domain truncation on cytokine production. These results demonstrate for the first time a direct functional role for serine phosphorylation in the alpha-chain of FcgammaRIa and suggest that the cytoplasmic domain of FcgammaRI regulates the different functional capacities of the FcgammaRIa-receptor complex.
Edberg
Jeffrey C
JC
Departments of Medicine and Microbiology, The University of Alabama at Birmingham, 1530 3rd Avenue S, THT433A, Birmingham, AL 35294, USA. JEdberg@uab.edu
Qin
Hongwei
H
Gibson
Andrew W
AW
Yee
Arthur M F
AM
Redecha
Patricia B
PB
Indik
Zena K
ZK
Schreiber
Alan D
AD
Kimberly
Robert P
RP
D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D051379:Mice; D019319:Okadaic Acid / Q000494:pharmacology; D010587:Phagocytosis; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
D019319:Okadaic Acid; D014443:Tyrosine