Molecular dissection of the FcRbeta signaling amplifier.
Human high affinity IgE receptors are expressed as two different isoforms: the tetrameric isoform, alphabetagamma(2), or the trimeric isoform, alphagamma(2). The alpha chain is the IgE binding subunit, whereas the FcRbeta and FcRgamma chains are the signaling modules. Both FcRbeta and FcRgamma contain immunoreceptor tyrosine-based activation motifs (ITAM), but the beta ITAM differs from canonical ITAMs in two ways; the spacing between the two canonical tyrosines harbors a third tyrosine, and it is one amino acid shorter than in canonical ITAMs, making it unfit to bind the tandem SH2 of Syk. We have shown that FcRbeta functions as an amplifier of the FcRgamma signaling function. However, the molecular mechanism of this amplification remains unclear. Here we show that mutation of the three tyrosines (Tyr-219, Tyr-225, and Tyr-229) in the beta ITAM essentially converts alphabetagamma(2)into an alphagamma(2) complex in terms of Lyn recruitment, FcRgamma phosphorylation, Syk activation, and calcium mobilization. Tyr-219 is the most critical residue in this regard. In addition, a detailed analysis of the dynamics of calcium mobilization suggests a possible inhibitory role for Tyr-225, which becomes apparent when Tyr-219 is mutated. Thus, the signaling amplification function of FcRbeta is mainly encoded in Tyr-219 and in its capacity to recruit Lyn. In turn, this Tyr-219-mediated Lyn recruitment enhances gamma chain phosphorylation, Syk activation, and calcium mobilization. The two other tyrosines appear to have a modulating function that remains to be fully assessed.
On
Marina
M
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Billingsley
James M
JM
Jouvin
Marie-Hélène
MH
Kinet
Jean-Pierre
JP
D020816:Amino Acid Motifs; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000737:chemistry* / Q000502:physiology; D015398:Signal Transduction; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism; D020298:U937 Cells; D019061:src-Family Kinases / Q000378:metabolism
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D017455:Receptors, IgE; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases