Journal of Leukocyte Biology Volume 60, October 1996 433 Protein tyrosine phosphorylation in leukocyte activation through receptors for IgG Carla Santana, Gino Noris, Bertha Espinoza, and Enrique Ortega Department of Immunology, Institu.to de investigaciones Biom#{233}dica,s, Universidad Naci.onal Au.t#{243}noma de Mexico, Cd. Universitaria, Mexico Abstract: Membrane receptors for the Fe portion of iinmunoglobulin G (IgG) antibodies (Fc’yRs) are expressed on almost every type of hematopoietic cells, where they mediate a wide variety of effector functions. A high degree of structural heterogeneity exists among FcyRs. The biological significance of such heterogeneity is unknown, since the structural diversity does not appear to be reflected in the binding specificity nor in the effector functions that each distinct receptor is able to mediate. Recent work has emphasized the essential role of protein tyrosine phosphorylation in the initiation of trans- membrane signaling by these receptors. In this article we review the role of protein tyrosine phosphoryla- tion in signal transduction by the different types of Fc’yRa in order to assess to what extent the structural heterogeneity of this receptor family is related to different activation pathways utilized by each of its members. J. Leukoc. Biol. 60: 433-440; 1996. Key Words: FcyR . transmembrane signaling . hematopoietic cells Membrane receptors for the Fe portion of immunoglobulin G (IgG) class antibodies (FcyRs) are expressed on almost every type of hematopoietic cells. Cross-linking of these receptors by aggregated IgG (in the forms of antigen-anti- body complexes, opsonized cells, or bacteria, etc.), triggers a very wide array of responses such as proliferation and differentiation, cell cytotoxicity, secretion of cytokines and inflammatory mediators, endocytosis, and phagocytosis, etc. Heterogeneity of these receptors was inferred early in their study, on the basis of differences in binding affinity of IgG to cells expressing IgG receptors, and in the differ- ent sensitivity of high- and low-affinity receptors to trypsin. Later, the development of monoclonal antibodies (mAbs) specific for the receptors and, more recently, the cloning and structural characterization of the genes encoding them, revealed a higher degree of heterogeneity than previously recognized. Currently known receptors for the Fe portion of IgG are classified into three groups: Fc’yRI, Fc’yRII, and FcyRIII, each of them comprising several individual recep- tor forms. The present classification is based on several criteria, including molecular size, expression on different cell types, recognition by distinct mAbs, and relatedness of the genes encoding them. A thorough review of the struc- ture of the genes, transcripts, and proteins of this family of receptors can be found in references 1-3. Despite the great progress achieved in defining the mo- lecular structure of the receptors and the genes encoding them, the functional and biological significance of the ob- served heterogeneity among FcyRs is largely unknown. Most of the heterogeneity among members of the FcyR family is found in the transmembrane and cytoplasmic re- gions, suggesting that it could be more related to the mechanisms of signal transduction than to interacting with different IgG subclasses. Indeed, the relative affinity of binding of human IgG subclasses to each of the FcyRs types follows very similar patterns: Fc’yRI, IgG3 IgGi > lgG4 >> IgG2; FcyRII, IgG3 IgGi >> IgG2, IgG4; and FcyRIII, IgG3 = IgGi >> IgG2, IgG4 [3, 4].It is still unclear whether, in distinct cell types, specific effector functions are mediated by only a particular class or isoform of FcyRs. However, with the exception of modulation of B cell activation by Fc’yRII bi and b2 isoforms, there is ample evidence indicating that many effector functions can be mediated by more than one particular type of Fey recep- tor. This has been established for phagocytosis of opson- ized particles and concomitant superoxide generation by FcyRII and FcyRIII on human neutmphils [5], phagocy- tosis of opsonized erythrocytes by murine FcyRII, and FcyRIII transfected into RBL-2H3 cells [6], phagocytosis mediated by each of Fc’yRI, Fc’yRII, or FcyRIII transfected into COS-1 cells [7], and antibody-dependent cell cyto- toxicity (ADCC) against target cells by distinct leukocytes [8], etc. The marked differences in the transmembrane and cyto- plasmic regions of receptors that have similar binding spe- cificities, and that mediate, to some extent at least, the same effector functions, might suggest that distinct recep- tors employ distinct biochemical transduction pathways. It has been known for some time that FcyR cross-linking induces several intracellular signals common to a variety Abbreviations: EgG, immunoglobulin C; mAbs, monoclonal antibodies; ITAM, immunoreeeptor tyrosine-based activation motifs; NK, natural killer; IFN-y, interferon-y; GPI, glycosyl-phosphatidylinositol; P13-K, phosphatidylinositol-3-kinase. Correspondence: Dr. Enrique Ortega, Department of Immunology, Instituto de Investigaciones Biom#{233}dicas, UNAM, Ap. Postal 70228, Cd. Universitaria, D.F., CP 04510, Mexico. Received January 22, 1996; revised April 23, 1996; accepted April 24, 1996.
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Journal of Leukocyte Biology Volume 60, October 1996 433
Protein tyrosine phosphorylation in leukocyte activation
through receptors for IgGCarla Santana, Gino Noris, Bertha Espinoza, and Enrique Ortega
Department of Immunology, Institu.to de investigaciones Biom#{233}dica,s, Universidad Naci.onal Au.t#{243}noma de Mexico,
Cd. Universitaria, Mexico
Abstract: Membrane receptors for the Fe portion
of iinmunoglobulin G (IgG) antibodies (Fc’yRs) are
expressed on almost every type of hematopoietic
cells, where they mediate a wide variety of effector
functions. A high degree of structural heterogeneity
exists among FcyRs. The biological significance of
such heterogeneity is unknown, since the structural
diversity does not appear to be reflected in the
binding specificity nor in the effector functions thateach distinct receptor is able to mediate. Recent
work has emphasized the essential role of protein
tyrosine phosphorylation in the initiation of trans-
membrane signaling by these receptors. In this article
we review the role of protein tyrosine phosphoryla-
tion in signal transduction by the different types of
Fc’yRa in order to assess to what extent the structural
heterogeneity of this receptor family is related to
different activation pathways utilized by each of its
contain FcyRIIa transcripts. In contrast, B cells do not
express FcyRIIa transcripts, but do express Fc’yRIIbl,
FcyRIIb2, and FcyRIIc transcripts. Myelomonocytic cells
contain mRNAs from all three FcyRII genes, including the
al, bl, b2, and c transcripts.
FcyRII has been shown to mediate phagocytosis, endo-
cytosis of Ag-Ab complexes, and ADCC in macrophages,
and a respiratory burst in neutrophils. In B cells (which
express only the b isoforms), co-cross-linking of FcyRII
with the BCR leads to diminished BCR signaling.
Although it has been reported that FcyRII on cultured
human monocytes can associate with y chains [37], the
association of FcyRII molecules with y or any other protein
has not been reproducibly found. In contrast to the cyto-
plasmic domains of FcyRI or FcyRIIIA, all three isoforms
of FcyRII contain in their cytoplasmic tail, tyrosines that
have been found to become phosphorylated upon receptor
aggregation. Moreover, these tyrosines have been shown to
be essential for mediating the effector functions (see be-
low). The FcyRIIa isoform contains the sequence D-G-G-
Y-M-T-L-X12-Y-L-T-L, which conforms to the consensus
ITAM motif except for a somewhat longer amino acid
stretch between the first and second tyrosine residues. The
bl and b2 isoforms contain a single (T/S)-X-X-Y-X-X-L
motif. This motif has been found to be essential for the
inhibition of BCR signaling, and thus the designation of
ITIM (immunoreceptor tyrosine-based inhibition motif) has
been proposed for this motif.
Several studies have comparatively analyzed the signal-
ing activities of different FcyRII isoforms in transfected
cells: Liu et al. [48] studied the induction of protein tyro-
sine phosphorylation by the a, bl, and b2 isoforms of hu-
man FcyRII transfected into mouse mastocytoma P815
cells, and found that only the a isoform was active. The
ability of different FcyRII isoforms to mediate phagocytosis
was also studied in transfected COS cells: FcyRIIa medi-
ated efficient binding and phagocytosis of IgG-coated
sheep red blood cells, whereas transfectants expressing
FcyRIIbl, Fc’yRIIb2, or a FcyRIIa mutant lacking the cy-
toplasmic tail, efficiently bind but did not ingest IgG-
coated erythrocytes [49]. Activity of the FcyRIIa isoform
was dependent on the integrity of both YXXL motifs [50].
Fc’yRIIa, but not the b isoforms, became tyrosine phospho-
rylated upon receptor activation. Interestingly, low levels
of phagocytosis were obtained with FcyRIIb2 and bi mu-
tants into whose cytoplasmic tail the FcyRIIa-isoform se-
quence YMTL, was introduced. The distinct activities of
FcyRIIa and FcyRIIb have also been analyzed upon trans-
fection into an FcR-negative B cell line IIA1.6 [51]. OnlyFcyRIIa was able to mediate phagocytosis of opsonized
bacteria and to trigger tyrosine phosphorylation. For both
these activities, the ITAM motif was critical. In contrast,
FcgRIIb isoforms induced tyrosine phosphorylation with
much slower kinetics, but only these receptors were capa-
ble of negatively regulating BCR-mediated signal
transduction, and their activity was dependent on an YSLL
(ITIM) motif. It has been recently shown that the modula-
tory effect of FcyRIIb1 is mediated by the recruitment and
activation of the tyrosine phosphatase P’l’PC 1, which binds
through its SH2 domain to the phosphorylated ITIM [52].
Cross-linking FcyRII has been shown to induce tyrosine
phosphorylation of several proteins, including the receptor
itself, and the association and activation of P’fKs of the Src
and syk families (Table 1 and references therein).
CONCLUSIONS AND PERSPECTIVES
Recent work summarized above has established the essen-
tial role that protein tyrosine phosphoiylation plays in the
initiation of transmembrane signaling by membrane recep-
tors of the FcyR family. With the exception of Fc’yRIIIB,
which do not have transmembrane and cytoplasmic do-
mains, all other membrane-bound Fc’y receptors appear to
employ a similar mechanism for signal transduction, in-
volving as a very early step, the phosphorylation of certain
tyrosine residues in the cytoplasmic domain of either the
IgG-binding chain or proteins associated with it. The criti-
cal tyrosines are part of either of two sequence motifs,
which have been called ITAM or ITIM (immunoreceptor
tyrosine-based inhibition motif) (Fig. 1). In both cases,
phosphorylation of the tyrosines within these motifs is nec-
essary for eliciting the functions associated with the recep-
tors.
The ITIM motif, which is found on Fc’yRIIbl and
FcyRIIb2 isoforms, is essential for the negative regulation
of BCR signaling in B cells. Mutation of the tyrosine or the
leucine of the ITIM motif eliminates the modulatory activ-ity [51]. Phosphorylation of the tyrosine mediates the asso-
ciation and concomitant activation of the protein
phosphatase PTP1C [52], which might dephosphorylate
Iga and Ig� subunits of the BCR, or kinases associated
with the complex, thus inhibiting its signaling activity.
ITAM motifs are found on the associated ‘yor � subunits of
the Fc’yRI and Fc’yRIIIA, and in the cytoplasmic tail of
Fc’yRIIa, and they play an essential role in signaling through
these receptors [53]. ITAM motifs are also found on the Igaand Ig�3 chains of the BCR, the y, 8, e, �, and TI chains of theTCR, and the y and f3 chains of the FccRI. Cross-linking of
the BCR, TCR, and FcERI, induces the phosphorylation oftyrosines within the ITAM motif, and this promotes the
association and concomitant activation of protein tyrosine
kinases of the Src and syk/ZAP-70 families. A similar
mechanism seems to operate upon cross-linking of FcyRI,
FcyRIIIA, and FcyRIIa, as both p72syk, as well as distinct
Src-family kinases have indeed been found associated to
FcyRs, and to be activated by FcyR aggregation (Table 1 and
references therein). The presence of a common signaling
motif on Fc’yRI, FcyRIIIA, and Fc’yRIIa, can explain the
observation that, when expressed on the same cell, structur-
ally distinct Fc’yR isoforms are able to mediate the same
functions. It seems improbable, however, that a family of
receptors, which are very homologous in their ligand binding
�‘ �Y,IY � viL � � V.
L LL V.
V
V
V
1. Ravetch, J. V., Kinet, J. P. (1991) Fe receptors. Anna. Rev. Immunol. 9,457-492.
2. Capel, P. J. A., van de Winkel, J. G. J., van den Herik-Oudijk, I.E., Verbeek,J. S. (1994) Heterogeneity of human IgG Fe receptors. Immunomethods 4,25-34.
3. Hulett, M. B., Hogan, P. M. (1994) Molecular basis of Fe receptor function.Adu. Immunol. 57, 1-127.
4. Ravetch, J. V., Anderson, C. L (1990) FcyR family: proteins, transcripts andgenes. In Pc Receptors and the Action of Antibodies (H. Metzger, ed.)
Washington, DC, Am. Soc. Microbiol., 211-235.
5. Durden, D. L., Rosen, H., Michel, B. R., Cooper,J. A. (1994) Protein tymsinephosphatase inhibitors block myeloid signal transduction through the FcyRlreceptor. Exp. Cell Res. 211,150-162.
6. Dacron, M., Malbec, 0., Latour, S., Bonnerot, C., Segal, D. M., Fndman, W.
H. (1993) Distinct intracytoplasmic sequences are required for endocytosisand phagocytosis via murine FcTRII in mast cells. fat. I,nmunot. 5,1393-1401.
7. Indik, Z. K., Park, J. G., Pan, X. Q., Schreiber, B. (1995) Induction of
phagocytosis by a protein tyrosine kinase. Blood 85, 1175-1180.8. Segal, D. M. (1990) Antibody-mediated killing by leukoeytes. talc Receptors
and the Action of Antibodies (H. Metzger, ed.) Washington, DC, Am. Soc.
Microbiol., 291-301.
438 Journal of Leukocyte Biology Volume 60, October 1996
I:y2 ha Ilbi IIb2 IIIA:y2 IIIA:�2
Fig. 1. Schematic representation of members of the FcyR family and
associated chains. Only those receptors containing cytoplasmic domains
are included. The length of the cytoplasmic tails of all chains is propor-
tional to the number of amino acid residues it contains.The position of
tyrosine residues that are part of ITAM motifs is indicated, as well as the
YSLL sequence of the ITIM motifs of FcTRIlb isoforms. The solid
rectangles represent the predicted transmembrane domains.
domains, but whose cytoplasmic domains are structurally
different, would have evolved to mediate always the same
functions, and the question remains as to what is the func-
tional significance of the high degree of structural diversity
found among Fcyreceptors.
An attractive possibility is that, although FcyRI, FcyRIIa,
and FcyRIII isoforms use phosphorylated ITAM motifs as
docking points for effector cytoplasmic molecules, the com-
position of the signaling complexes assembled by the dis-
tinct receptors might be different. This may result from
differences in the amino acids near the consensus tyrosines
and leucines/isoleucines of the ITAM motif, which can
dictate a preferential association with distinct SH2-contain-
ing proteins (Src or syk kinases [54], or possibly other
effector molecules), as have been shown for the different sets
of proteins that bind to phosphorylated ITAM motifs of the
Igcx and Ig� chains of the BCR [55], and to phosphorylated yand f� chains of the FcERI [56]. The assembling of different
signaling complexes by each receptor isoform can result in
the triggering of different biochemical pathways.
Another important point to be noted is that the specific-
ity of the interactions of a particular ITAM-containing se-
quence with different SH2-containing proteins, does not
seem to be absolute. It has been shown that in cells defi-
cient of a given Src kinase, other members of the family
can substitute for it [57]. It is also evident from the data in
Table 1 that the y subunit can associate with both hck and
lyn in human monocytes, and the ITAM of Fc’yRIIa can
associate with at least three distinct Src family members:
fyn, lyn, and Fgr. This promiscuity in interactions of phos-
phorylated ITAMs with Src family kinases can endow thesystem with a certain degree of plasticity, by allowing the
coupling of the same receptor isoform to distinct activation
pathways on different cells, depending on the expression
levels of the various different proteins capable of interact-
ing with the phosphorylated ITAMs. Indeed, it has been
recently shown that p72syk, but not the related kinase
ZAP-70, stimulated FcyRIIIA mediated phagocytosis in
transfected COS-l cells, but ZAP-70 increased phagocy-tosis if coexpressed with the Src family kinase Fyn [54].
Despite the great progress achieved in recent years in the
molecular characterization of FcyRs, and in establishing the
role of tyrosine phosphorylation in signal transduction by
#{149}.,, these receptors, several questions remain unanswered, espe-
“ cially those related to the functional significance of the high
degree of heterogeneity found among this family of receptors.
The next step forward for understanding the initiation of
effector functions mediated by this family of receptors,
would depend on a full characterization of the composition
and pathways activated by the signaling complexes assem-
bled after receptor cross-linking, involving the IgG binding
chains, associated subunits, associated kinases and phos-
phatases, and substrates of them. Of special importance is
the realization that different signaling complexes might beassembled by the same receptor isoform under different
conditions, depending not only on the cell type involved, but
also probably on the activation or metabolic state of the cell.
It is not unreasonable to think that stimuli different from IgG
complexes, such as cytokines or hormones, might regulate
effector functions mediated by FcyRs by affecting the ex-
pression not only of receptor isoforms, but also of different
kinases and the substrates upon which they act.
ACKNOWLEDGMENTS
This work was supported by grants from the Direcci#{243}n
General de Asuntos del Personal Acad#{233}mico, UNAM
(1N205792 and IN204293), and from CONACyT (1072-N9201).
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