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Mediates B Cell Receptor Constitutive Internalization1
*
CJF 9501 and
Unité 255, INSERM and
UMR 144 CNRS, Molecular Mechanisms of Intracellular Trafficking Laboratory, Institut Curie, Paris;
§
Laboratoire d’Histocompatibilité, Centre Régional de Transfusion Sanguine and
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INSERM Unité 74, Institut de Virologie, Faculté de Médecine, Strasbourg; and
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Centre d’Immunologie INSERM-CNRS de Marseille-Luminy, Marseille, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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/Ig
ß heterodimers. One main BCR function is to bind and to internalize
Ags. Peptides generated from these internalized Ags may be presented to
T lymphocytes. Here, we have analyzed the involvement of BCR Ig /Ig
ß components in BCR constitutive endocytosis. The role of Ig
subunit in BCR constitutive endocytosis was first determined in the
context of an IgM-based BCR. In contrast with BCR that contain
wild-type Ig , surface BCR lacking Ig cytoplasmic domain were
not constitutively internalized. The respective roles of Ig and Ig
ß subunits were then analyzed by expressing chimeric molecules
containing the cytoplasmic domains of either subunits in a B cell line.
Only the Ig cytoplasmic domain contained an internalization signal
that allowed constitutive endocytosis of Ig chimeras via coated
pits and accumulation in sorting-recycling endosomes. This
internalization signal is contained in its immunoreceptor
tyrosine-based activation motif. These results indicate that Ig ,
through its immunoreceptor tyrosine-based activation motif, may account
for the ability of IgM/IgD BCR to constitutively internalize monovalent
Ags. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß heterodimer
(for review, see 9 that is shared by the five mIg isotypes (10).
The cytoplasmic domain of mIgG contains a tyrosine-based
internalization signal (7) that allows Ag presentation via this
specific BCR (11). However, mIgM and mIgD, whose cytoplasmic domains
are restricted to only three amino acids, are nevertheless able to
endocytose Ag and allow presentation of Ag-derived peptides to
CD4+ T cells (12, 13). Consequently, an internalization
signal may lie in the Ag receptor-associated /ß heterodimers. The
two subunits of these dimers contain a structural motif (ITAM) in their
cytoplasmic tail that is conserved among a family of
receptor-associated molecules specialized in immune recognition,
including CD3-
, -
,, -
, -
, FcRI, and FcRIII
(14). This motif, which contains two tyrosine residues, mediates a
variety of receptor functions (15), including endocytosis (16, 17). It
has recently been shown that the cytoplasmic domain of Ig ß was
sufficient to promote an efficient presentation of polyvalent Ags when
fused to mIg extracellular and transmembrane domains (8). We recently
demonstrated that both Ig and Ig ß cytoplasmic tails promote
internalization of multivalent Ags, but lead to different pathways of
class II-restricted Ag presentation (18). Nevertheless, the two
tyrosine residues in the Ig ß sequence do not appear to be essential
for the internalization of multivalent ligands (8). To date, no
information is available on the relative roles of the Ig and Ig ß
subunits in the constitutive endocytosis of the BCR and, consequently,
on the internalization and presentation of monovalent Ags.
To characterize the role of Ig in BCR endocytosis, we used
the Ig -deficient myeloma cell line J558Lµm (19), which has been
reconstituted with wild-type or a truncated form of Ig that lacks
the intracytoplasmic tail (20). We show that the Ig intracellular
domain is necessary to promote BCR constitutive endocytosis. The Ig
internalization signal was further analyzed using chimeric molecules
consisting of the extracellular and transmembrane domains of FcRII
and the cytoplasmic domain of either Ig or Ig ß subunits (18, 21). These chimeric molecules were expressed in a FcR-defective B
lymphoma cell line, IIA1.6. Efficient constitutive endocytosis only
occurred with the Ig chimeras (c.Ig ). Morphologic studies
showed that c.Ig was distributed between the plasma membrane and
compartments containing internalized recycling transferrin (Tf),
whereas c.Ig ß accumulated at the cell surface. A mutational analysis
showed that the constitutive internalization signal was dependent on
the first tyrosine residue of the Ig ITAM. The identification of
this constitutive internalization signal is the first step in
understanding the molecular basis of monovalent Ag uptake by
BCR.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NHS-SS-biotin, NHS-LC-biotin, streptavidin coupled to horseradish peroxidase, and streptavidin-agarose beads were purchased from Pierce Chemcial Co. (Rockford, IL). Other chemicals used in this study were obtained from Sigma Chemical Co. (St. Louis, MO). RPMI 1640, FCS, PBS, penicillin, streptomycin, sodium pyruvate, nonessential amino acids, and L-glutamine were purchased from Life Technologies (Paisley, Scotland). RPMI depleted of methionine and 35S Trans-label were obtained from ICN (Costa Mesa, CA). Protein A-Sepharose and cyanogen bromide-activated Sepharose 4B were purchased from Pharmacia (Uppsala, Sweden). Tf was coupled to FITC as previously described (22).
Plasmid construction and transfection
Ig and Ig ß chimeras were constructed by adding the
cytoplasmic domains of Ig and Ig ß to the extracellular and
transmembrane domains of cDNA encoding FcRII as previously described
(23). The tail minus FcR (FcR/IC-) was described previously (16).
The deletion in the cytoplasmic tail of Ig or Ig ß as well as the
tyrosine mutants were constructed by recombinant PCR and then
sequenced. The resulting amino acid sequences of the cytoplasmic tails
of all the constructs are shown in Table II
. The cDNA encoding the
chimeric proteins were inserted in SR-driven expression vector that
also contains the neomycin resistance gene. Vectors were linearized
with ScaI enzyme before transfection into the B lymphoma
cell line IIA1.6 as previously described (23). After selection in
G418-containing medium, 50 to 100% of the selected cells expressed
FcR chimeras screened with the rat anti-mouse FcR mAb 2.4G2
(24). When necessary, FcR-positive cells were selected by panning
with 2.4G2.
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The B lymphoma IIA1.6, a FcR-defective variant of the A20 B
cell, was grown in RPMI 1640 medium containing 50 mM 2-ME, 5 mM sodium
pyruvate, and 10 mM glutamine and supplemented with 10% FCS. The
J558Lµm mb1-transfected cells were provided by M. Reth and grown as
previously described (20). Rabbit antiserum directed against the
exoplasmic portion of the IgG FcR were provided by C. Sautes. 20.8.4s
is an anti-Kd mAb. Texas Red- and FITC-labeled
donkey IgGs directed against rabbit and rat IgGs were purchased from
Immunotech (Marseille, France).
Constitutive endocytosis of cell surface biotinylated proteins
Cells (107) were pulse labeled, then chased for
2 h at 37°C, and surface biotinylated with a solution containing
25 mg of NHS-SS-biotin in 3 ml of PBS at 4°C, with prior incubation
at 37°C for indicated times. After chilling at 4°C, biotin
remaining at the cell surface was or was not stripped with 1 ml of a
solution containing 1.55 mg of glutathione, 150 mM NaCl, 10% FCS, and
5 ml of 50% NaOH or containing 20 mM 2-mercaptoethanesulfonic acid
(MESNA), 50 mM Tris (pH 8.6), 100 mM NaCl, and 0.2% BSA. Cells were
lysed in 500 µl of lysis buffer, and biotinylated proteins were
sequentially precipitated first with the Ag NIP coupled to Sepharose 4B
(for the IgM) or with the rabbit antiserum directed against the
extracellular domain of FcR coupled to protein A-Sepharose (for
chimeras) and then with streptavidin-agarose for both (18).
Biotinylated proteins were finally dissociated from
streptavidin-agarose beads by boiling in Laemmli’s sample buffer under
reducing conditions and were resolved by SDS-PAGE.
Immunofluorescence
Cells were first allowed to adhere on glass coverslips precoated
with a 0.1% poly-L-lysine solution in water. Cells
were fixed in 3% paraformaldehyde for 10 min at room temperature.
After permeabilization with 0.05% saponin in PBS supplemented with
0.2% BSA, they were incubated with specific Abs and processed as
previously described (18). When specified, adherent cells were
incubated with 10 µg/ml of 2.4G2 mAb for 30 min at 4°C. They were
then incubated for 30 min at 37°C and treated as described above for
intracellular staining. Permeabilized cells were incubated with a
rabbit serum directed against the mouse FcR portion of the chimeric
molecules (anti-FcR) and finally stained with both FITC- and
Texas Red-labeled donkey antisera directed against, respectively, rat
and rabbit IgGs. FITC-transferrin endocytosis was performed as
previously described (22).
Confocal microscopy
Confocal laser scanning microscopy and double immunofluorescence analysis were performed using a TCS4D confocal microscope based on a DM microscope interfaced with a mixed gas argon/krypton laser (Leica Laser Technik, Heidelberg, Germany). Simultaneous double fluorescence acquisitions were performed using the 488 and 568 nm laser lines to excite FITC and Texas Red dyes with a x100 oil immersion Neofluar objective (numerical aperture = 1.3). The fluorescence was selected with appropriate double fluorescence dichroic mirror and bandpass filters and measured with blue-green-sensitive and red-sensitive side 1 photomultipliers.
Electron microscopy
The c.Ig and c.Ig ß cells were cooled on ice for 15 min
and then incubated with 2.4G2 mAb directly coupled to 12-nm gold
particles for 1 h at 4°C. Abs were coupled to gold particles
(25). Cells were then fixed as previously described (26). Briefly, an
equal volume of cold 3% glutaraldehyde in 0.1 M Na cacodylate buffer
containing 1% sucrose, pH 7.3, was added to cells for 1 h. After
centrifugation, the cell pellet was resuspended in 1.5% glutaraldehyde
in cacodylate buffer. Cells were then prepared for transmission
electron microscopy as previously described (26). For quantitative
analysis, cell surfaces were examined systematically, noting the
location of every gold particle encountered.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cytoplasmic tail
We first evaluated the endocytic properties of the Ig and Ig
ß BCR subunits in IgM-positive (IgM anti-NIP) J558Lµm cells
expressing either wild-type (wt) or cytoplasmic tail-deleted Ig (Ig
IC) (20).
To follow the endocytosis of surface IgM, metabolically labeled cells
were surface biotinylated with cleavable NHS-SS-biotin at 4°C and
further incubated at 37°C for various times. To quantify the relative
amounts of internalized IgM, each sample was divided into two equal
aliquots; one of which was treated with MESNA at 4°C, a
membrane-impermeant reducing agent. The residual cell-associated biotin
corresponded to proteins protected from reduction by internalization.
IgM were first precipitated with NIP-BSA coupled to Sepharose beads.
The biotinylated IgM were then isolated by a second step of
precipitation with streptavidin-agarose beads. Our results showed that
the surface IgM were constitutively internalized in the wt cells (Fig. 1a), as assessed by the
detection of increasing amounts of protected biotinylated IgM. A
plateau representing 35 to 40% of internalized IgM was reached within
10 to 20 min of incubation at 37°C (Fig. 1b). In
contrast, the Ig IC cells showed no BCR constitutive
internalization. The level of constitutive TfR internalization was
equivalent in the two cell lines (data not shown). We concluded that
the Ig cytoplasmic domain is necessary to trigger IgM-based BCR
constitutive endocytosis.
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chimeras are constitutively internalized molecules
The constitutive internalization of the two BCR-associated
subunits was further analyzed in B cells (IIA1.6) expressing chimeras
where Ig or Ig ß intracellular domains were fused to the
transmembrane and extracellular domains of the mouse FcRII (c.Ig
and cIg ß; Table I). We therefore
analyzed their rate of endocytosis essentially as described in Figure 1
. Chimera-expressing cells were metabolically labeled, and cell
surface proteins were biotinylated with cleavable NHS-SS-biotin at
4°C before incubation at 37°C for various times. Only c.Ig was
efficiently internalized (Fig. 2a), as assessed by the
increasing amount of protected biotinylated c.Ig after incubation
at 37°C. In this set of experiments, equilibrium was reached between
10 and 20 min of incubation at 37°C. The size of the pool of
internalized c.Ig was 40 to 45% (Fig. 2b). In
contrast, lower amounts of c.Ig ß were internalized, as the
intracellular pool after 30 min at 37°C was 5% (Fig. 2b). In c.Ig -transfected cells, MHC class I
H-2Kd molecules were sequentially immunoprecipitated, and
no internalization was detected (Fig. 2, b and
c). The endocytosis of the mIgGs expressed on c.Ig
ß-transfected cells was examined. The amount of internalized mIgG
reached a plateau at 25% (Fig. 2, b and
c) within 10 to 20 min at 37°C. The different sizes
of the cIg and cIg ß intracellular pools suggested that the
cytoplasmic tail of Ig contains an internalization signal that
mediates constitutive endocytosis of mIgs (7). However, we could not
exclude that the both chimera were efficiently internalized, with cIg
addressed to degradative compartments and Ig ß quickly recycling
back to the cell surface.
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and Ig ß
chimeras in pulse-chase experiments. The appearance of both molecules
at the plasma membrane was followed by biotinylation of the cell
surface at various chase times, ranging from 0 to 6 h. Within 30
min to 1 h, most of the newly synthesized cIg or cIg ß
molecules was terminally glycosylated, as assessed by their reduced
mobility in SDS-PAGE compared with that at the zero time point (Fig. 2c). No variation in the signal intensities was
observed within the next 6 h, showing that degradation did not
occur. As shown in the right panel of Figure 2c,
both cIg and cIg ß reached the cell surface, where they were
biotinylated within the first hour after their synthesis, and no
significant variation in signal for biotinylated molecules was observed
during the next 5 h. We therefore concluded that both chimera had
similar stability, and that, probably, the differences in the
intracellular pool sizes observed in Figure 2b were due to a
more efficient constitutive internalization of the Ig chimera.
To further investigate this question, we next examined whether the
cytoplasmic tail of Ig and Ig ß determined the differential
recruitment of the chimera in clathrin-coated pits, which is the first
step of receptor internalization. Cells were immunolabeled with
gold-coupled 2.4G2 mAb directed against the FcR extracellular domain of
the chimeras and prepared for examination by electron microscopy (Fig. 3). Quantitative analysis of the
distribution of c.Ig chimeric molecules at the cell surface showed
that 12% of all gold particles were located inside or in the vicinity
of clathrin-coated pits (Table I). In contrast, only 1.7% of gold
particles coupled to the 2.4G2 mAb decorated such structures on the
plasma membrane of c.Ig ß-transfected cells. These data show that the
Ig cytoplasmic domain allows the chimeras to be enriched up to
sevenfold in coated pits (Table II). Therefore, only the cytoplasmic
domain of the Ig subunit of the Ig /ß sheath determined
recruitment in coated pits and constitutive internalization of BCR.
Since these chimera seemed stable in pulse-chase experiments (Fig. 2c), these data suggested that after internalization,
Ig chimera were recycled back to the cell surface.
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molecules accumulated in Tf-containing endosomal
compartments
We first analyzed the steady state distribution of Ig and Ig
ß chimeras by immunofluorescence microscopy (Fig. 4) after cell surface permeabilization.
The chimera were labeled with rabbit anti-FcR IgGs and Texas
Red-coupled secondary Abs. The c.Ig was clearly distributed between
the plasma membrane and cytoplasmic structures (Fig. 4a). In contrast, c.Ig ß was essentially
accumulated at the cell surface, as shown in a medial optical slice of
labeled cells (Fig. 4b). We then characterized the
intracellular compartments where c.Ig chimeric molecules
accumulated using double immunofluorescence and confocal microscopy. As
a sorted and recycling endosomal marker, FITC-coupled Tf (FITC-Tf) was
continuously internalized for 30 min at 37°C before cell fixation
(Fig. 4c). The c.Ig were labeled with rabbit
anti-FcR IgGs and Texas Red-coupled secondary Abs (Fig. 4d). FITC-Tf was distributed between plasma membrane
and vesicular intracellular structures that were also positive for
anti-FcR staining. Double labelings with later markers of the
endosomal pathway such as cathepsin D and cation-independent
mannose-6-phosphate receptor were also performed, but no clear
colocalization was observed (not shown). Therefore, c.Ig were
constitutively endocytosed and were probably recycled to the
surface.
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is located in its
ITAM and is dependent on tyrosine 23
To better characterize the internalization signal of Ig , we
analyzed the cell surface behavior of mutant molecules in which the
cytoplasmic domain was essentially constituted by the ITAM (c.Ig m;
Table I). The c.Ig m was still
efficiently internalized (Fig. 5a), and its cellular
distribution (Fig. 5b) was identical with that
observed for c.Ig (Fig. 2a). In contrast,
chimeric molecules containing only the ITAM flanking sequences showed
none of these characteristics (not shown). Together, these results
showed that Ig ITAM is sufficient to promote the constitutive
internalization of the hybrid molecules and their intracellular
distribution between plasma membrane and endosomal compartments.
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ITAM were
part of the endocytosis signal. These tyrosine residues were separately
mutated into alanines in the c.Ig m chimeras (c.Ig mA23 and c.Ig
mA34; Table I). We found that the mutation of the first tyrosine
abolished the constitutive internalization of the chimeras (c.Ig
mA23), whereas the mutation of tyrosine 34 had no effect (c.Ig
mA34; Fig. 5a). As expected from the above
results, c.Ig mA23 (Fig. 5c) accumulated at the
plasma membrane of IIA1.6-transfected cells, whereas c.Ig mA34 (Fig. 5d) distributed between plasma membrane and internal
vesicles. In conclusion, the membrane-proximal tyrosine residue of Ig
ITAM involved in the B cell receptor activation pathway (20) is
also part of a tyrosine-based signal for constitutive endocytosis. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Ig ß subunits in the
constitutive internalization of IgM-based BCR.
Using B lymphoma cells expressing mutated Ig in the context of the
BCR or expressing Ig chimeric molecules, we have shown that the
cytoplasmic tail of the Ig subunit determines the size of the
intracellular pool of BCR or of Ig chimera, respectively. In
addition, electron microscopy demonstrated that the Ig cytoplasmic
tail determined the recruitment of the chimera in coated pits. We
therefore conclude that the cytoplasmic tail of Ig contains a
constitutive internalization signal. In J558Lµm-transfected cells,
the Ig intracytoplasmic tail is therefore necessary for surface IgM
constitutive internalization. Interestingly, the size of the steady
state pool of internalized c.Ig (40–45%) was similar to that of
BCR (30–45%) in the J558Lµm cells, but higher than that obtained in
a mouse spleen cell population or in mIgM-expressing mouse cell lines
(10%) (8). It may be possible that the mIg internalization rates
depend on the cell type, but even with a small rate, monovalent Ags
could be efficiently internalized due to multiple recycling of mIg (7).
Morphologically, we demonstrated that at the steady state, c.Ig is
accumulated in intracellular compartments labeled for internalized Tf,
while c.Ig ß was essentially detected at the plasma membrane. Most
c.Ig molecules clearly colocalized with internalized recycling Tf,
indicating that mIgs are recycling proteins through their Ig
subunits.
Our results showed that mIgM constitutive internalization is totally
dependent on Ig . However, the activity of Ig may depend on the
mIg isotype. Indeed, the 2a cytoplasmic tail contains an
internalization signal that promotes the internalization of mIgG2a (31)
and efficient Ag presentation (11). However, this signal functions
after mIgG2a cross-linking. It is not known whether it also works as a
signal for mIg constitutive endocytosis. The c.Ig and Ig ß
chimeric molecules are able to efficiently internalize immune complexes
and allow presentation of peptides (18). It was also shown that B cells
expressing a mutant IgM molecule that does not interact with Ig /Ig
ß dimers were inefficient for Ag presentation (32). Ig and Ig ß
subunits may thus cooperate with each other as well as with Ig heavy
chains to regulate internalization and presentation of various forms of
Ags via a complete BCR, especially with respect to the multivalency of
these Ags.
The cytoplasmic domains of the /ß sheath polypeptides
contain a tyrosine-based activation motif (ITAM) shared by other Ag
receptor tails (14). We previously showed that in the FcRIII
-chain this motif is essential for both efficient internalization of
immune complexes and Ag presentation (16). It was also shown that in
the case of this receptor, the two ITAM tyrosines are necessary for Ag
presentation (16). In contrast, mutations of equivalent tyrosine
residues in the Ig ß chain do not alter the capacity of
internalization of polyvalent Ags (8). We show here, by deleting the
ITAM-flanking sequences, that this motif was sufficient to promote
constitutive endocytosis of cIg . We also demonstrate that the first
ITAM tyrosine residue was required for constitutive internalization.
However, this mutation does not impair the internalization of
multivalent ligand (unpublished observation). Therefore,
internalization of monovalent or polyvalent Ags may involve different
signals within the BCR complexes.
It has been shown in vitro that tyrosine-polar-polar-hydrophobic
(YppØ) amino acid sequences directly interact with the µ2 protein of
the endocytosis machinery (33, 34), probably allowing localization in
clathrin coated-pits and constitutive internalization of the receptors
bearing these motifs. Both Ig and Ig ß BCR chains contain two
putative YppØ sequences. We have shown that only Ig concentrates
into coated pits and that only the membrane-proximal YxxL sequence
functions as an endocytosis signal. It suggests that the specificity of
the interactions between the YppØ sequences and components of the
endocytic machinery probably resides in the structural context of these
motifs.
The relative exclusion of c.Ig ß from plasma membrane-coated pits indicates that cytoplasmic proteins might be responsible for the low internalization efficiency of this chimeric molecule. Src-related kinases are candidate regulatory proteins for this process, as shown for p56lck, which prevents the constitutive internalization of CD4 (35). Although the mechanism by which p56lck is involved is not yet clear, p56lck may interact with components of the cortical cytoskeleton (36) and thus may serve to anchor CD4 to the plasma membrane and to cytoskeletal proteins. Understanding the mechanisms by which the different polypeptides of the BCR cooperate with each other and with other intracellular molecules should clarify how specific Ags are targeted to the specific intracellular compartment where class II molecules are competent for peptide binding.
The intracellular compartment where peptide loading of MHC class II
molecules takes place in B cells is now better characterized and seems
to be distinct from conventional compartments of the
endosomal-recycling pathway (37, 38, 39, 40). This compartment is accessible to
Ag bound to mIgs but not to Tf, although processing may be initiated
within the sorting-recycling compartments (40). It implies that
internalized Ag-BCR complexes contain specific sorting information for
being targeted to this compartment. Such sorting information was found
in the cytoplasmic tail of the 2a chain for multivalent Ags (11).
The present study shows that at least the first step in this process
for monovalent Ags, namely internalization, depends on specific
sequences present in the Ig polypeptide chain. We previously showed
that Ig and Ig ß contain sufficient information to drive
polyvalent Ags toward different intracellular pools of MHC class II
molecules (18). Together, these data suggest that targeting of
monovalent or polyvalent Ags toward MHC class II-competent compartments
may involve distinct components of the BCR complex.
Our knowledge of BCR structure is far from complete. The interaction of
Ig and Ig ß with distinct cytoplasmic molecules, including the
endocytic machinery, is submitted to modulation by the valency of the
ligand. This indicates that BCR-mediated Ag endocytosis, targeting, and
further processing may be regulated according to the physiologic
requirements of the immune response.
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Acknowledgments |
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Footnotes |
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2 Both authors contributed equally to this work.
3 Present address: The Rockefeller University, Laboratory of Molecular Immunology, 1230 York Ave., New York, NY 10021.
4 Address correspondence and reprint requests to Dr. C. Bonnerot, CJF INSERM 9501, Institut Curie, 26 rue D’Ulm, 75248 Paris Cedex 05, France. E-mail address:
5 Abbreviations used in this paper: BCR, B cell Ag receptor; mIg, plasma membrane Ig; ITAM, immunoreceptor tyrosine-based activation motif; FcR, receptor for the Fc portion of IgG; c.Ig /ß, chimeric molecules between exoplasmic-transmembrane domains of Fc receptor and cytoplasmic tails of Ig- or -ß; Tf, transferrin; MESNA, 2-mercaptoethanesulfonic acid; wt, wild-type; TfR, transferrin receptor; FITC-Tf, FITC-coupled transferrin; Ii, invariant chain associated to class II molecules of the MHC.
Received for publication May 5, 1997. Accepted for publication November 3, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/ß sheath and occurs independently of its cytoplasmic tyrosines. Cell 74:939.[Medline]
and Ig ß subunits in MHC class II-restricted antigen presentation. Immunity 3:335.[Medline]
and Ig-ß but the activation of protein tyrosine kinases does. Eur. J. Immunol. 24:665.[Medline]
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M. Kraus, L. I. Pao, A. Reichlin, Y. Hu, B. Canono, J. C. Cambier, M. C. Nussenzweig, and K. Rajewsky Interference with Immunoglobulin (Ig){alpha} Immunoreceptor Tyrosine-based Activation Motif (ITAM) Phosphorylation Modulates or Blocks B Cell Development, Depending on the Availability of an Ig{beta} Cytoplasmic Tail J. Exp. Med., August 20, 2001; 194(4): 455 - 470. [Abstract] [Full Text] [PDF]
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R. Muller, J. Wienands, and M. Reth The serine and threonine residues in the Ig-alpha cytoplasmic tail negatively regulate immunoreceptor tyrosine-based activation motif-mediated signal transduction PNAS, July 18, 2000; 97(15): 8451 - 8454. [Abstract] [Full Text] [PDF]
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E. San Jose and B. Alarcon Receptor Engagement Transiently Diverts the T Cell Receptor Heterodimer from a Constitutive Degradation Pathway J. Biol. Chem., November 19, 1999; 274(47): 33740 - 33746. [Abstract] [Full Text] [PDF]
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A. Borroto, J. Lama, F. Niedergang, A. Dautry-Varsat, B. Alarcon, and A. Alcover The CD3{epsilon} Subunit of the TCR Contains Endocytosis Signals J. Immunol., July 1, 1999; 163(1): 25 - 31. [Abstract] [Full Text] [PDF]
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B. K. Brown, C. Li, P. C. Cheng, and W. Song Trafficking of the Igalpha /Igbeta Heterodimer with Membrane Ig and Bound Antigen to the Major Histocompatibility Complex Class II Peptide-loading Compartment J. Biol. Chem., April 16, 1999; 274(16): 11439 - 11446. [Abstract] [Full Text] [PDF]
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