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The Journal of Immunology, 1998, 161: 5129-5132.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Role of the Inositol Phosphatase SHIP in B Cell Receptor-Induced Ca2+ Oscillatory Response1

Hidetaka Okada*, Silvia Bolland{dagger}, Akiko Hashimoto{ddagger},§, Mari Kurosaki*, Yukihito Kabuyama, Masamitsu Iino{ddagger},§, Jeffrey V. Ravetch{dagger} and Tomohiro Kurosaki2,*

* Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Japan; {dagger} Laboratory of Molecular Genetics and Immunology, Rockefeller University, New York, NY 10021; {ddagger} Department of Pharmacology, Faculty of Medicine, University of Tokyo, Tokyo Japan; § Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan; and Department of Biomolecular Sciences, Fukushima Medical College, Fukushima, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Src homology-2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP) is a recently identified protein that has been implicated as an important signaling molecule. Although SHIP has been shown to participate in the Fc{gamma}RIIB-mediated inhibitory signal, the functional role of SHIP in activation responses by immunoreceptor tyrosine-based activation motif-bearing receptors such as B cell receptor (BCR) remains unclear. Indeed, it has been proposed that SHIP serves as a linking molecule for the regulation of the extracellular signal-regulated kinase pathway in BCR signaling, because SHIP associates with Shc. We now report that SHIP-deficient DT40 B cells display enhanced Ca2+ mobilization in response to BCR ligation, whereas extracellular signal-regulated kinase activation is unaffected. This Ca2+ enhancement is due to a sustained intracellular Ca2+ increase or to long-lasting Ca2+ oscillations by loss of SHIP, as revealed by single-cell Ca2+ imaging analysis. These results demonstrate the importance of SHIP in B cell activation by the modulation of Ca2+ mobilization.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The binding of a foreign Ag to B cell receptor (BCR)3 is the critical step in B cell activation, because it initiates a cascade of intracellular signaling events. (1, 2, 3, 4). One of the signaling events following BCR stimulation is an increase in the intracellular Ca2+ concentration ([Ca2+]i), which is mediated primarily by inositol 1,4,5-trisphosphate (IP3) receptors (5). Ca2+ may also enter the cytoplasm by a process termed capacitative Ca2+ entry or store-operated Ca2+ influx, by which the depletion of intracellular stores by IP3 activates Ca2+ influx across the plasma membrane (6, 7, 8). BCR stimulation also leads to extracellular signal-regulated kinase (ERK) activation, which in turn activates transcription factors. Analogous to receptor tyrosine kinases, the interaction of Grb-2, Shc, and Sos, which has been implicated in the activation of Ras, is a potential pathway for ERK activation after BCR ligation (2).

The BCR signal is negatively regulated by coligation to Fc{gamma}RIIB (9). Recent studies have shown that Src homology-2 domain-containing inositol polyphosphate 5'-phosphatase (SHIP) is recruited to the phosphorylated immunoreceptor tyrosine-based inhibitory motif in the Fc{gamma}RIIB cytoplasmic tail upon cocross-linking of BCR and Fc{gamma}RIIB, leading to inhibition of the BCR-elicited signal (10). Apart from the role of SHIP in the Fc{gamma}RIIB-mediated inhibitory signal, SHIP might be involved in the BCR signal itself, because SHIP is tyrosine-phosphorylated and associates with Shc and Grb-2 upon BCR ligation alone (11, 12, 13). Here, we addressed this issue by analyzing DT40 B cells deficient in SHIP. The BCR-induced Ca2+ signal was significantly augmented by a loss of SHIP, whereas ERK activation was unaffected. Moreover, this Ca2+ augmentation was dependent upon the enzymatic activity of SHIP. Thus, our data suggest that SHIP plays a role in BCR signaling as well as in the Fc{gamma}RIIB-mediated inhibitory signal.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cells, expression constructs, and Abs

Wild-type (wt) and SHIP-deficient DT40 cells were cultured as described previously (5). cDNA of mouse SHIP possessing mutations in the inositol 5'-phosphatase catalytic domain (P671A, D675A, and R676G) was generated by PCR and subcloned into expression vector pApuro (5). The following Abs were used: anti-chicken IgM mAb M4 (µ, {kappa}) (14) and anti-SHIP Ab (10).

Generation of SHIP-deficient DT40 cells

A chicken cDNA library (Clontech, Palo Alto, CA) was screened by the mouse SHIP cDNA (10), and chicken genomic SHIP clones were obtained by PCR. Targeting vectors were constructed by replacing the genomic fragment containing exons that correspond to mouse SHIP amino acid residues 121–224 with blasticidin S- and hygromycin-resistant gene cassettes. Selection was performed as described previously (5). A single clone of the SHIP-deficient mutants was extensively analyzed, although some critical experiments were conducted using at least two different clones.

Northern blot analysis

Total RNA (20 µg) was separated in a 1.2% formaldehyde gel, transferred to a Hybond-N+ nylon membrane (Amersham, Arlington Heights, IL), and probed with 32P-labeled cDNAs.

Immunoprecipitation and Western blot analysis

The wt and SHIP-deficient cells were solubilized in lysis buffer as described previously (5). Precleared lysates were sequentially incubated with Abs and protein A-agarose. Lysates or immunoprecipitates were separated by SDS-PAGE, transferred to a nitrocellulose membrane, and detected by appropriate Abs using the enhanced chemiluminescence system (Amersham).

In vitro kinase assay of ERK

Stimulated DT40 cells were immunoprecipitated by anti-ERK Ab (Santa Cruz Biotechnology, Santa Cruz, CA). Immunoprecipitated ERK was suspended in kinase buffer (20 mM HEPES (pH 7.4), 2 mM DTT, 10 mM MnCl2, 10 mM MgCl2, and 0.01 mM sodium vanadate) containing [{gamma}-32P]ATP (>3000 Ci/mmol; New England Nuclear, Boston, MA). Glutathione S-transferase-Elk fusion protein (5 µg per one immunoprecipitate) was added as a substrate (15), and the reaction mixture was incubated at 30°C for 20 min.

Ca2+ measurements

Ca2+measurements were performed as described previously (5). For single-cell Ca2+ imaging analysis, cells that had been cultured for 1 day on coverslips were incubated with 5 µM fura-2/acetoxymethyl ester (Molecular Probes, Eugene, OR) for 30 min at room temperature in standard buffer solution (16). The coverslips with the fura-2-loaded cells were mounted on the stage of an inverted epifluorescence microscope (model TMD 300, Nikon, Tokyo, Japan). Cells were examined under a x40 water immersion objective (numerical aperture 0.7) and were illuminated with 340 and 380 nm lights, alternately. Fluorescence images at 520 nm were collected using a cooled charge-coupled device camera (model PXL-37, Photometrics, Tucson, AZ) at 2 frames per second.

Phosphoinositide analysis

Cells (106/ml) were labeled with myo-[3H]inositol (10 µCi/ml) (Amersham) for 12 h in inositol-free RPMI 1640 medium supplemented with 10% dialyzed FCS. Next, cells (1 x 107/ml) were stimulated with mAb M4. The soluble inositol phosphate was extracted with TCA and separated by HPLC (17).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
In addition to the function of SHIP in the Fc{gamma}RIIB-mediated inhibitory signal, the findings that SHIP is able to bind phosphorylated immunoreceptor tyrosine-based activation motifs such as Fc{epsilon}RI ß and TCR {zeta} chains in vitro have provided a possibility that SHIP is also used as a signaling molecule in the immunoreceptor tyrosine-based activation motif-dependent signaling pathway (18, 19). To test this possibility, we took a genetic approach and used the SHIP-deficient DT40 B cell line. A lack of SHIP expression was confirmed by Northern and Western blot analyses (Fig. 1Go, A and B). The level of cell surface expression of BCR on SHIP-deficient clones was essentially the same as that of parental DT40 cells (data not shown). One of the earliest events following BCR stimulation is the induction of tyrosine kinase activity. SHIP-deficient DT40 cells did not show substantial differences in the overall increase of tyrosine phosphorylation upon BCR cross-linking, except SHIP itself. The extent of tyrosine phosphorylation of SHIP upon BCR engagement was significantly decreased compared with that seen upon coligation of the BCR and Fc{gamma}RIIB (data not shown).



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  		FIGURE 1. Disruption of the SHIP gene in chicken B cell line DT40. A, RNA expression analysis using chicken cDNA probes for SHIP (top) or ß-actin (bottom). B, Western blot analysis of SHIP protein expression in wt and targeted DT40 cells. Cells were lysed and immunoprecipitated with anti-SHIP Ab. These immunoprecipitates were separated by 8% SDS-PAGE; the blotted membrane was incubated with anti-SHIP Ab.

 
Ca2+ mobilization is another hallmark of BCR-induced signaling. The fura 2-loaded SHIP-deficient and wt DT40 cells were stimulated with the anti-BCR mAb M4, and the rise in intracellular Ca2+ ([Ca2+]i) was measured. The peak height and the duration of a [Ca2+]i increase upon receptor stimulation were ~1.7- and 2-fold, respectively, and were enhanced by the loss of SHIP (Fig. 2GoA). In the presence of EGTA, little enhancement of [Ca2+]i increase was observed in SHIP-deficient cells compared with wt DT40. To further clarify the effects of SHIP on BCR-induced Ca2+ mobilization, we analyzed the Ca2+ response in more detail using single-cell Ca2+ imaging analysis. The responses of five representative individual cells are shown in Fig. 2GoB. The [Ca2+]i increase in wt single cells was significantly attenuated with time after BCR stimulation, whereas Ca2+ mobilization was sustained in SHIP-deficient cells; a significant [Ca2+]i increase remained even after 220 s following the M4 application, demonstrating that the absence of SHIP allows B cells to manifest a more sustained BCR-driven increase in [Ca2+]i. As for the peak levels of the initial [Ca2+]i increase, there is no significant difference between wt and SHIP-deficient single cells (620 ± 20 nM vs 670 ± 30 nM, respectively) (mean ± SEM of 140 cells from seven cultures in each cell line). The time between M4 application and the initial peak [Ca2+]i increase differed from cell to cell, but the average values were almost the same between wt and SHIP-deficient cells (37.4 ± 1.3 s and 40.0 ± 3.1 s, respectively) (140 cells from each cell line). These observations indicate that the calcium onset after BCR stimulation is not affected by loss of SHIP.



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  		FIGURE 2. Ca2+ mobilization, IP3 generation, and IP4 generation in wt and SHIP-deficient DT40 cells. A, Intracellular free Ca2+ levels in fura-2-loaded cells were monitored by a spectrophotometer following stimulation with M4 (2 µg/ml). Ca2+ release from intracellular Ca2+ stores was measured in the presence of 1 mM EGTA (+EGTA). B, Single-cell [Ca2+]i imaging analysis. [Ca2+]i changes in five representative cells within the same imaging field are shown for wt cells (left) and SHIP-deficient cells (right). The application of M4 (2 µg/ml) through a puffing pipette was initiated at the time indicated by the arrows. C, For IP3 and IP4 detection, soluble inositol was extracted from cells stimulated with M4 (2 µg/ml) and analyzed by HPLC. Data are shown as the fold increase of the value before stimulation with M4. Results are expressed as the mean from three independent experiments. Error bars represent the SD from the mean.

 
Since IP3 is primarily important for BCR-induced Ca2+ mobilization through its binding to IP3 receptors (5), we determined IP3 generation after BCR stimulation. As shown in Fig. 2GoC, SHIP-deficient DT40 cells showed similar kinetics of BCR-induced IP3 generation in comparison with wt cells, although the stimulation fold was slightly increased compared with wt cells. In addition to IP3, inositol 1,3,4,5-tetrakisphosphate (IP4) has been proposed to participate in Ca2+ signaling (20). This model is particularly attractive, because SHIP has been shown to hydrolyze IP4 in vitro (13, 21). Thus, the enhancement of Ca2+ mobilization in SHIP-deficient cells might be accounted for by the increased level of IP4 in the mutant cells. Similar to IP3 generation, the BCR-induced IP4 level in SHIP-deficient DT40 cells was slightly increased (Fig. 2GoC).

It has been proposed that SHIP may regulate the ERK pathway via its association with the adaptor protein Shc (11, 12, 13). To examine this possibility, we analyzed ERK activation in wt and SHIP-deficient DT40 cells. As shown in Fig. 3Go, the BCR-induced ERK activation was almost the same level as that seen in wt DT40 cells, as revealed by an in vitro kinase assay.



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  		FIGURE 3. ERK activation in wt and SHIP-deficient cells. Cells were stimulated with M4 (4 µg/ml). Stimulated cells were immunoprecipitated with anti-ERK Ab. Immunoprecipitates were divided, and one-half were used for the in vitro kinase assay. Samples were electrophoresed by 12% SDS-PAGE and autoradiographed. The remaining half were used for Western blotting with anti-ERK Ab.

 
To test the requirement of phosphatase activity in BCR signaling, we transfected wt and phosphatase mutant SHIP into SHIP-deficient DT40 cells. Transformants expressing similar levels of wt and mutant SHIP (Fig. 4GoA) were isolated and analyzed. Upon BCR stimulation, SHIP-deficient cells expressing wt SHIP showed normal Ca2+ mobilization, whereas enhanced Ca2+ mobilization was not corrected by the SHIP phosphatase mutant (Fig. 4GoB). These results demonstrate that SHIP enzymatic activity is required for normal BCR-induced Ca2+ mobilization.



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  		FIGURE 4. Transfection of wt and phosphatase mutant SHIP into SHIP-deficient DT40 cells. A, Expression of transfected wt and phosphatase mutant SHIP in SHIP-deficient DT40 cells. Cells were lysed and electrophoresed by 8% SDS-PAGE. The blotted membrane was incubated with anti-SHIP Ab. B, Ca2+ mobilization of BCR signaling by SHIP mutant. SHIP-deficient DT40 cells expressing wt and the phosphatase mutant are indicated as wt/SHIP- and P-/SHIP-, respectively. Ca2+ mobilization was conducted as described in Fig. 2GoA.

 
We have shown that Ca2+ mobilization is significantly augmented by loss of SHIP, whereas ERK activation is unaffected. What is the underlying mechanism that explains the enhanced Ca2+ mobilization by the loss of SHIP? Our data, when taken together with the evidence that wortmannin inhibits BCR-induced Ca2+ mobilization (22), indicate that phosphatidylinositol 3,4,5-trisphosphate (PI-3,4,5-P3) is a critical mediator for Ca2+ modulation. Scharenberg and Kinet have recently proposed that calcium influx is regulated by PI-3,4,5-P3-dependent IP3 generation (23). Thus, one possibility is that the small difference of IP3 generation between wt and SHIP-deficient DT40 cells may affect Ca2+ mobilization through their proposed model. However, given the evidence that there is at least a 10-fold difference in the IP3 concentration that is required for releasing Ca2+ from intracellular stores or for opening the store-operated calcium channel (calcium release-activated calcium current) (24), an alternative interpretation is that PI-3,4,5-P3 regulates the store-operated Ca2+ influx process independently of IP3.

Transcriptional regulator NF-{kappa}B and c-Jun N-terminal protein kinase are selectively activated by a large transient [Ca2+]i rise, whereas NF of activated T cells is activated by a low, sustained Ca2+ plateau; this observation suggests that the amplitude and duration of Ca2+ signals contribute to transcriptional specificity (25). Thus, regulation of Ca2+ mobilization patterns by SHIP could be one mechanism of modulating the B cell activation state.


   Acknowledgments
 
We thank Dr. K. Hirose for comments on single-cell Ca2+ analysis, Dr. M. Miyamoto for helping with the isolation of chicken SHIP cDNA, Ari Hashimoto for establishing the in vitro kinase assay of ERK, and Dr. Y. Homma for helping with HPLC analysis.


   Footnotes
 
1 This work was supported by grants to T.K. from the Ministry of Education, Science, Sports, and Culture of Japan, the Ciba-Geigy Foundation (Japan), the Naito Foundation, and the Toray Science Foundation; to M.I. from the Ministry of Education, Science, Sports, and Culture of Japan; and to J.V.R. from the National Institutes of Health. S.B. is the recipient of an S.L.E. Foundation Career Development Award. Back

2 Address correspondence and reprint requests to Dr. Tomohiro Kurosaki, Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570-8506, Japan. E-mail address: Back

3 Abbreviations used in this paper: BCR, B cell receptor; SHIP, Src homology-2 domain-containing inositol polyphosphate 5'-phosphatase; wt, wild type; ERK, extracellular signal-regulated kinase; IP3, inositol 1,4,5-trisphosphate; IP4, inositol 1,3,4,5-tetrakisphosphate; PI-3,4,5-P3, phosphatidylinositol 3,4,5-trisphosphate. Back

Received for publication July 13, 1998. Accepted for publication September 10, 1998.


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