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(Received for publication, March 13, 1995; and in revised form, May 9, 1995) From the
Hematopoietic cell phosphatase is a nonreceptor protein tyrosine
phosphatase that is preferentially expressed in hematopoietic cell
lineages. Motheaten mice, which are devoid of (functional)
hematopoietic cell phosphatase, have severe disturbances in the
regulation of B cell activation and differentiation. Because signals
transduced via the B cell antigen receptor are known to guide these
processes, we decided to analyze molecular interactions between the
hematopoietic cell phosphatase and the B cell antigen receptor.
Ligation of the B cell antigen receptor induces moderate tyrosine
phosphorylation of hematopoietic cell phosphatase and the formation of
a multimolecular complex containing additional 68-70- and 135-kDa
phosphoproteins. In resting B cells most of the hematopoietic cell
phosphatase proteins reside in the cytosolic compartment, whereas after
B cell antigen receptor cross-linking, a small fraction translocates
toward the membrane where it specifically binds to the 135-kDa
phosphoprotein. This 135-kDa glycoprotein was identified as CD22, a
transmembrane associate of the B cell antigen receptor complex.
Together these findings provide the first direct evidence that this
cytoplasmic tyrosine phosphatase is involved in antigen
receptor-mediated B cell activation, suggesting that in vivo B
cell antigen receptor constituents or associated molecules may serve as
substrate for its catalytic activity.
Antigen receptor-mediated B cell activation critically depends
on the regulated activities of both protein tyrosine kinases and
protein tyrosine phosphatases. Early after BCR ( In
contrast to the considerable number of protein tyrosine kinase that are
known to be involved in BCR signaling, studies on the contribution of
protein tyrosine phosphatase have so far been restricted to the CD45
protein. Expression of CD45 is required for BCR signaling, because
BCR-induced tyrosine phosphorylation is severely affected in B cells
lacking CD45(10) . The recent observation that CD45 may be
physically associated with the BCR supports this notion(11) . A
potential role for a second class of protein tyrosine phosphatase was
suggested by the recent identification of the intracellular protein
tyrosine phosphatase 1C-hematopoietic cell phosphatase (HCP) (12) and Syp (protein tyrosine phosphatase 1D)(13) .
HCP is mainly expressed in cells of hematopoietic origin, whereas Syp
is ubiquitously expressed. Both protein tyrosine phosphatases are
characterized by the presence of two SH2 domains, which provide them
with the capacity to become recruited toward tyrosine-phosphorylated
substrates(14, 15) . Interestingly, Motheaten mice and
viable Motheaten mice, which do not express or express aberrant forms
of HCP protein, respectively(16, 17) , are
characterized by defects in lymphocyte development, including premature
thymic involution, impaired mitogen and alloantigen-induced T cell
responses, and diminished numbers of B cell
precursors(18, 19) . Clinically, Motheaten mice suffer
from severe autoimmune diseases and severe combined immunodeficiency
syndromes(20) . At present, the molecular role of HCP in B cell
signaling and differentiation is unknown. Because signals transmitted
via the BCR are known to guide B cell development and differentiation,
we decided to analyze the possible involvement of HCP in BCR signaling.
Figure 1:
BCR cross-linking induces tyrosine
phosphorylation of HCP and the formation of a multimolecular HCP
complex. Following incubation with or without 5 µg/ml biotinylated
µH chain mAb (CLB MH-15), Daudi cells were stimulated for 3 min in
Hepes medium containing streptavidin. Subsequently, cells were lysed in
Nonidet P-40 immunoprecipitation buffer, and after preclearing, the HCP
proteins were isolated with HCP antibodies. The immunoprecipitates were
separated on SDS-PAGE, transferred to nitrocellulose membranes, probed
with phosphotyrosine mAb (RC20, upper panel), and visualized
by enhanced chemiluminescence. The symbols represent: HCP (arrow), phosphoprotein 68-70 (arrow*), and
phosphoprotein 130-135 (◂). Subsequently, the membrane was
reprobed with HCP antibodies (lower panel). Four separate
experiments gave similar results.
Figure 2:
Distinct HCP complexes are localized in
the membrane and cytosolic fraction. Daudi cells were stimulated for
the indicated periods of time as described in Fig. 1and, prior
to lysis, subcellular fractions were prepared by sonication. Next, HCP
proteins were specifically recovered from the precleared membrane (m) and cytosolic (c) fractions and analyzed in
anti-phosphotyrosine (upper panel) and anti-HCP Western blots (lower panel). Symbols are used as described in Fig. 1.
Three additional experiments gave similar
results.
Figure 3:
The
HCP-associated 135-kDa glycoprotein comigrates with CD22. HCP and CD22
were specifically isolated from lysates of Daudi cells following
activation as described in Fig. 1. Subsequently, the
immunoprecipitates were separated by SDS-PAGE either directly (left
panel) or after treatment with N-glycanase (right
panel), and analyzed in anti-phosphotyrosine Western blots. Two
additional experiments gave similar
results.
Figure 4:
HCP
is associated with tyrosine-phosphorylated CD22. HCP and CD22 were
specifically isolated from lysates of Daudi cells following activation
as described in Fig. 1. The immunoprecipitates were separated by
SDS-PAGE and analyzed in anti-phosphotyrosine Western blots (upper
panel). Subsequently, the membrane was reprobed with HCP
antibodies (lower panel). Densitometric analysis indicated
that CD22-bound HCP represented 5-10% of the directly isolated
HCP proteins. Two additional experiments gave similar
results.
The present finding
that HCP serves as a substrate for BCR-induced protein tyrosine kinase
activity, together with the identification of tyrosine-phosphorylated
CD22 as the specific docking site for HCP within the BCR complex,
provides the first direct evidence for a role of this cytoplasmic
tyrosine phosphatase in BCR signaling. Likely, one or more
phosphotyrosine-incorporating motifs within the CD22 cytoplasmic tail
directly mediate the interaction with one or both SH2 domains of HCP.
Indeed, some of these CD22 motifs share homology with the recently
described erythropoietin receptor-derived phosphopeptides that display
binding specificity for the amino-terminal SH2 domain of
HCP(27, 29) . The recruitment of HCP via CD22 into the
BCR complex suggests that one or more BCR constituent(s) and/or
associated tyrosine- phosphorylated proteins may serve as substrate for
its tyrosine phosphatase activity. So far, we failed to detect
substantial protein tyrosine phosphatase activity of HCP directed
against BCR constituents in vitro (data not shown). However,
the recent observation that recombinant HCP has the capacity to
dephosphorylate the IL-3 receptor Previous studies
in Motheaten mice, which lack HCP protein, have demonstrated the
importance of HCP in B cell
differentiation(18, 20, 33) . Interestingly,
most of the B cells in these mice belong to the CD5 BCR-induced protein tyrosine
kinase activation results in tyrosine phosphorylation of several
accessory molecules, including CD5(23) , CD19(40) , and
CD22(31) , creating potential binding sites for SH2
domain-containing proteins. Indeed, it has been shown that
tyrosine-phosphorylated CD19 serves as a specific and preferential
binding site for the 85-kDa subunit of phosphatidylinositol 3-kinase (40) . Our present finding that CD22 specifically recruits HCP
provides further support for this function of accessory molecules.
Thus, accessory molecules appear to have a dual function. They have the
capacity to cooperate with the BCR at the extracellular level in the
process of antigen recognition(41, 42) . In addition,
they provide the BCR with molecular substrates to couple to specific
intracellular activation pathways.
Note Added in
Proof-After acceptance of the manuscript, similar data have
been reported by Campbell, M. A., and Klinman, N. R. (1995) Eur. J.
Immunol.25, 1573-1579 and Doody et al.
(Doody, G. M., Justement, L. B., Delibrias, C. C., Matthews, R. J.,
Lin, J., Thomas, M. L., and Fearon, D. T.(1995) 269, 242-244).
Volume 270,
Number 35,
Issue of September 01, pp. 20305-20308, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)cross-linking a large number of cellular proteins become
phosphorylated on tyrosine residues(1) . This change in
phosphorylation status of cellular proteins has two potential
consequences. First, it may alter the enzymatic activity of certain
proteins (e.g. PLC (2) ). Second, the induction
of tyrosine phosphorylation provides a mechanism to accomplish specific
interactions with SH2 domain-containing proteins and can result in an
altered subcellular distribution of proteins or protein
complexes(3) . It has been shown previously that two types of
PTK are physically and functionally associated with the BCR. These
include the src family members lyn, fyn, blk, and lck(4, 5) and the
ZAP70-related PTK syk(6, 7, 8, 9) .
Cells
The Burkitt lymphoma cell line Daudi was
routinely cultured in Iscove's modified Dulbecco's medium
supplemented with 10% fetal calf serum and antibiotics. Tonsillar B
cells were isolated from tonsils of healthy donors and purified as
described previously (21, 22) .Antibodies
The mAb specific for µH chain
(CLB-MH15), CD3 (CLB-T3.4/2a), CD14 (CLB-mon/1), CD16 (CLB-FcRgran/1),
CD19 (CLB-CD19), CD22 (CLB-CD22), and HLA-Dr (CLB-HLA-DR) were
generated at the CLB (Amsterdam, The Netherlands). The H chain mAb
(
TA-4) was obtained from the ATCC. Antibodies directed against
phosphotyrosine (RC20) and Shc were from Signal Transduction
Laboratories (Lexington, KY), and phosphatidylinositol 3-kinase
antibodies were purchased from Upstate Biotechnology, Inc. (Lake
Placid, NY). Antibodies specific for HCP were obtained from Santa Cruz
Biotechnology (Santa Cruz, CA).
Immunoprecipitation and Western Blotting
Intact
cells and subcellular fractions were lysed with IMMUNOPRECIPITATION
BUFFER (final concentration, 1% Nonidet P-40, 0.01 M
triethanolamine-HCl, pH 7.8, 0.15 M NaCl, 5 mM EDTA,
1 mM 1-chloro-3-tosylamido-7-amino-2-heptanone, 0.02 mg/ml
ovomucoid trypsin inhibitor, 1 mM phenylmethylsulfonyl
fluoride, 0.02 mg/ml leupeptin, 0.4 mM vanadate, 10 mM NaF, 10 mM pyrophosphate, 25 µM phenylarsine
oxide) as described previously(22) . Postnuclear debris and
subcellular fractions were precleared by three incubations with 50
µl of a 10% (v/v) suspension of protein A-CL4B Sepharose beads
(Pharmacia Biotech Inc.) coated with nonimmune mouse Ig, and once with
protein A-Sepharose. Next, cell lysates were sequentially incubated
with specific antibodies (15 min) and protein A-Sepharose (1.5 h).
After washing in immunoprecipitation buffer, the immunoprecipitates
were resuspended in sample buffer and separated on SDS-PAGE. Western
blotting was performed as described previously(23) . In short,
after transfer to Hybond C nitrocellulose blots (Amersham Corp.),
employing a semidry electroblotting chamber (Multiphore II, Pharmacia)
and blocking with 1% bovine serum albumin (Organon, Oss, The
Netherlands), the proteins were detected with specific antibodies.
Immunoreactive proteins were visualized by enhanced chemiluminescence
(ECL, Amersham; POD, Boehringer Mannheim). For sequential analysis of
the same blot with distinct antibodies, deprobing was performed
according to the manufacturer's instructions.B Cell Activation
The cells were washed twice in
Hepes solution (132 mM NaCl, 6 mM KCl, 1 mM MgSO
, 1 mM CaCl
, 1.2 mM KHPO, 20 mM Hepes, pH 7.4,
supplemented with 0.5% human serum albumin and 0.1% glucose) and kept
at 4 °C. Subsequently, the cells were incubated with purified
biotinylated mAb for 3 min, pelleted by rapid centrifugation, and
resuspended in Hepes solution containing 25 µg/ml streptavidin at
37 °C for the indicated period of time. Following activation, the
cells were either pelleted and lysed or resuspended in ice-cold
sonication buffer.Subcellular Fractionation
Following stimulation, B
cells (2-3 107) were resuspended in ice-cold sonication
buffer (5% w/v sucrose, 10 mM Hepes, 1 mM EGTA in
phosphate-buffered saline, supplemented with protease and phosphatase
inhibitors). After sonication of the suspension (3
15 s at 21
kHz frequency and 9 µm peak-to-peak amplitude) and removal of
unbroken cells and nuclei, 1 ml of postnuclear supernatant was layered
on a discontinuous sucrose gradient consisting of 1.5 ml of 40% (w/v)
sucrose and 1.5 ml of 15% (w/v) sucrose. After centrifugation (35,000
g, 50 min), 80% of the supernatant (as source of
cytosol) and the interface of the sucrose layers (as source of
membranes) were collected and analyzed as indicated
elsewhere(24) .
BCR Cross-linking Induces Tyrosine Phosphorylation of
HCP and the Formation of a Multimolecular HCP Complex
Previous
reports have indicated that HCP may serve as substrate for src family protein tyrosine kinase(25, 26) . Since
the BCR is functionally and physically coupled to several of these src family protein tyrosine kinase we have analyzed whether
BCR ligation results in tyrosine phosphorylation of HCP. HCP was
isolated from activated and nonactivated Daudi cells and was
subsequently analyzed in anti-phosphotyrosine blots. Following
activation, a moderately tyrosine phosphorylated HCP protein was
detected that migrated with an apparent molecular mass of 65 kDa (Fig. 1, upper panel (arrow)). This protein
reacted with anti-HCP antibodies (Fig. 1, lower panel).
An additional tyrosine phosphorylated protein (arrow*) was
visualized that migrated only slightly slower than HCP but was
nonreactive with anti-HCP antibodies (Fig. 1, lower
panel). Next to HCP and the 68-70-kDa protein a very
prominent tyrosine-phosphorylated protein with an apparent molecular
mass of 130-135 kDa (◂) was detected in anti-HCP
immunoprecipitates following BCR cross-linking. Similar results were
obtained when HCP was isolated from tonsillar B cells (data not shown).
Subcellular Distribution of Activation-induced HCP
Complexes
Several studies have demonstrated that HCP interacts
with tyrosine-phosphorylated transmembrane receptors in an
activation-dependent manner(14, 15, 27) .
Similarly, the phosphoproteins detected in anti-HCP immunoprecipitates
might represent constituents of the BCR complex that serve to recruit
HCP toward potential substrates associated with the BCR complex. When
the anti-HCP immunoprecipitates were analyzed in anti-phosphotyrosine
blots, HCP complexes with distinct features were observed in membrane
and cytosolic fractions, respectively (Fig. 2, upper
panel). Most of the HCP proteins resided in the cytosolic
fraction, although after activation a slight decrease was observed (Fig. 2, lower panel). In activated B cells, cytosolic
HCP proteins were moderately phosphorylated on tyrosine residues (arrow) and were associated with the 68-70-kDa
phosphoprotein (arrow*). However, a small amount of the HCP
proteins (5-10%) was detected in the membrane fraction. In
contrast to what was observed in the cytosolic fraction, neither
tyrosine phosphorylation of the HCP protein nor of the 68-70-kDa
protein was detected in the membrane fraction. Although it can not be
excluded that the tyrosine phosphorylation of HCP proteins residing in
the membrane fraction is below detection level, these findings argue
against a preferential membrane translocation of tyrosine
phosphorylated HCP proteins, which appears to be the case for Shc
proteins(22, 28) .
Tyrosine-phosphorylated CD22 Acts as Membrane Target for
HCP
In marked contrast to the 68-70-kDa phosphoprotein,
the tyrosine-phosphorylated 130-135-kDa phosphoprotein was
exclusively detected in association with the membrane-translocated HCP
protein (Fig. 2, ◂), indicating that this phosphoprotein
possibly represents the membrane target of HCP. The fact that this
130-135-kDa phosphoprotein was not detected in HCP complexes from
activated Jurkat cells (data not shown) suggested that this protein
could be a B cell-specific transmembrane molecule. Among the B
cell-specific transmembrane molecules that serve as a substrate for
BCR-induced protein tyrosine kinase activity and are known to be
involved in BCR signaling, the BCR complex-associated CD22 appeared to
be a possible candidate(29, 30) . To investigate this
hypothesis, anti-HCP and CD22 immunoprecipitates were isolated from
activated Daudi cells, and half of each immunoprecipitate was directly
analyzed in anti-phosphotyrosine blots. In accordance with previous
reports, CD22 was detected as a 135-kDa tyrosine-phosporylated protein (Fig. 3, left panel)(31) . Comparison with the
HCP-associated 135-kDa phosphoprotein demonstrated that both proteins
migrated at the same position in the SDS-PAGE, both under nonreducing (Fig. 3, left panel) and reducing conditions (data not
shown). Treatment of the remaining half of the immunoprecipitates with N-glycanase prior to analysis in anti-phosphotyrosine blots
revealed that both CD22 and the HCP-associated 135-kDa protein were
deglycosylated and then still migrated at the same position following
SDS-PAGE (Fig. 3, right panel). The apparent molecular
mass of 100-105 kDa corresponds with the reported protein
backbone of CD22(32) . Definite evidence for the interaction of
CD22 with HCP was obtained when CD22 immunoprecipitates, isolated from
activated B cells, were analyzed in anti-HCP blots. In agreement with
the subcellular fractionation experiments (see Fig. 2) only a
small part of the total amount of HCP protein was found to interact
with CD22 (Fig. 4). Densitometric analysis indicated that
5-10% of the total cellular HCP pool may associate with CD22 upon
activation. The observation that in these parallel immunoprecipitations
the phosphotyrosine content of HCP-associated CD22 is comparable with
that of directly isolated CD22 suggests that most of the
tyrosine-phosphorylated CD22 is bound by HCP.
-chain, c-fms and
c-kit in vitro provides a precedent for this
possibility(14, 15) . The involvement of the
phosphorylation status of HCP in its protein tyrosine phosphatase
activity is still unresolved. The IL-3-induced association between the
IL-3 receptor -chain and HCP occurs without any significant
alteration in HCP tyrosine phosphorylation and activity, while a
marginal induction of HCP tyrosine phosphorylation was detected
following c-fms and c-kit ligation, again without
effect on its activation status. Our experiments indicate that
tyrosine-phosphorylated HCP is preferentially localized in the
cytosolic compartment (Fig. 2-4). Therefore tyrosine
phosphorylation of HCP might facilitate the potential interactions with
other cytosolic proteins incorporating SH2 domains. subset, which is thought to be responsible for the production of
autoreactive antibodies(34) . Several studies have reported
structural and functional differences between the BCR in CD5
and conventional B cells,
respectively(23, 35, 36, 37, 38) .
This may indicate that BCR signals required for differentiation of the
former subset operate relatively independent of HCP or that the
presence of CD5 within the BCR complex somehow compensates for this
defect. However, another explanation could be that HCP is involved in
the BCR-mediated deletion of autoreactive B cells. Lack of HCP
expression might thus deregulate this selection process. Recently,
Cyster and Goodnow (39) have provided evidence that such a
mechanism may indeed be operative.
)
We thank Prof. D. Roos and Dr. A. J. Verhoeven for
critical reading of manuscript.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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