Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B Cells

AbstractWe showed that Eμ-MiR-155 transgenic mice develop acute lymphoblastic leukemia/high-grade lymphoma. Most of these leukemias start at approximately 9 months irrespective of the mouse strain. They are preceded by a polyclonal pre–B-cell proliferation, have variable clinical presentation, are transplantable, and develop oligo/monoclonal expansion. In this study, we show that in these transgenic mice the B-cell precursors have the highest MiR-155 transgene expression and are at the origin of the leukemias. We determine that Src homology 2 domain–containing inositol-5-phosphatase (SHIP) and CCAAT enhancer-binding protein β (C/EBPβ), 2 important regulators of the interleukin-6 signaling pathway, are direct targets of MiR-155 and become gradually more down-regulated in the leukemic than in the preleukemic mice. We hypothesize that miR-155, by down-modulating Ship and C/EBPβ, initiates a chain of events that leads to the accumulation of large pre-B cells and acute lymphoblastic leukemia/high-grade lymphoma.

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APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl

Leukemia ◽

10.1038/sj.leu.2401397 ◽

1999 ◽

Vol 13 (5) ◽

pp. 760-767 ◽

Cited By ~ 30

Author(s):

T Wakioka ◽

A Sasaki ◽

K Mitsui ◽

M Yokouchi ◽

A Inoue ◽

...

Keyword(s):

Adaptor Protein ◽

Pleckstrin Homology ◽

Sh2 Domains ◽

Src Homology 2 ◽

Src Homology ◽

Stat Pathway

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p135 Src Homology 2 Domain-containing Inositol 5′-Phosphatase (SHIPβ) Isoform Can Substitute for p145 SHIP in FcγRIIB1-mediated Inhibitory Signaling in B Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m003714200 ◽

2000 ◽

Vol 275 (39) ◽

pp. 29960-29967 ◽

Cited By ~ 6

Author(s):

Michael E. March ◽

David M. Lucas ◽

M. Javad Aman ◽

Kodimangalam S. Ravichandran

Keyword(s):

B Cells ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain ◽

Inhibitory Signaling

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A Dual Role for Src Homology 2 Domain–Containing Inositol-5-Phosphatase (Ship) in Immunity

Journal of Experimental Medicine ◽

10.1084/jem.191.5.781 ◽

2000 ◽

Vol 191 (5) ◽

pp. 781-794 ◽

Cited By ~ 115

Author(s):

Cheryl D. Helgason ◽

Christian P. Kalberer ◽

Jacqueline E. Damen ◽

Suzanne M. Chappel ◽

Nicolas Pineault ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Lymphoid Development ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain ◽

B Lymphoid

In this report, we demonstrate that the Src homology 2 domain–containing inositol-5-phosphatase (SHIP) plays a critical role in regulating both B cell development and responsiveness to antigen stimulation. SHIP−/− mice exhibit a transplantable alteration in B lymphoid development that results in reduced numbers of precursor B (fraction C) and immature B cells in the bone marrow. In vitro, purified SHIP−/− B cells exhibit enhanced proliferation in response to B cell receptor stimulation in both the presence and absence of Fcγ receptor IIB coligation. This enhancement is associated with increased phosphorylation of both mitogen-activated protein kinase and Akt, as well as with increased survival and cell cycling. SHIP−/− mice manifest elevated serum immunoglobulin (Ig) levels and an exaggerated IgG response to the T cell–independent type 2 antigen trinitrophenyl Ficoll. However, only altered B cell development was apparent upon transplantation into nonobese diabetic–severe combined immunodeficient (NOD/SCID) mice. The in vitro hyperresponsiveness, together with the in vivo findings, suggests that SHIP regulates B lymphoid development and antigen responsiveness by both intrinsic and extrinsic mechanisms.

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Distribution of the Src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells

Biochemical Journal ◽

10.1042/0264-6021:3420697 ◽

1999 ◽

Vol 342 (3) ◽

pp. 697 ◽

Cited By ~ 29

Author(s):

Eric MURAILLE ◽

Xavier PESESSE ◽

Céline KUNTZ ◽

Christophe ERNEUX

Keyword(s):

B Cells ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain ◽

Haemopoietic Cells

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Differential Regulation of B Cell Development, Activation, and Death by the Src Homology 2 Domain–Containing 5′ Inositol Phosphatase (Ship)

Journal of Experimental Medicine ◽

10.1084/jem.191.9.1545 ◽

2000 ◽

Vol 191 (9) ◽

pp. 1545-1554 ◽

Cited By ~ 96

Author(s):

Anne Brauweiler ◽

Idan Tamir ◽

Joseph Dal Porto ◽

Robert J. Benschop ◽

Cheryl D. Helgason ◽

...

Keyword(s):

Bone Marrow ◽

B Cells ◽

B Cell ◽

Cell Development ◽

B Cell Development ◽

Inositol Phosphatase ◽

Src Homology 2 ◽

Src Homology ◽

Src Homology 2 Domain ◽

Deficient Mice

Although the Src homology 2 domain–containing 5′ inositol phosphatase (SHIP) is a well-known mediator of inhibitory signals after B cell antigen receptor (BCR) coaggregation with the low affinity Fc receptor, it is not known whether SHIP functions to inhibit signals after stimulation through the BCR alone. Here, we show using gene-ablated mice that SHIP is a crucial regulator of BCR-mediated signaling, B cell activation, and B cell development. We demonstrate a critical role for SHIP in termination of phosphatidylinositol 3,4,5-triphosphate (PI[3,4,5]P3) signals that follow BCR aggregation. Consistent with enhanced PI(3,4,5)P3 signaling, we find that splenic B cells from SHIP-deficient mice display enhanced sensitivity to BCR-mediated induction of the activation markers CD86 and CD69. We further demonstrate that SHIP regulates the rate of B cell development in the bone marrow and spleen, as B cell precursors from SHIP-deficient mice progress more rapidly through the immature and transitional developmental stages. Finally, we observe that SHIP-deficient B cells have increased resistance to BCR-mediated cell death. These results demonstrate a central role for SHIP in regulation of BCR signaling and B cell biology, from signal driven development in the bone marrow and spleen, to activation and death in the periphery.

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Adaptor Protein 3BP2 Is a Potential Ligand of Src Homology 2 and 3 Domains of Lyn Protein-tyrosine Kinase

Journal of Biological Chemistry ◽

10.1074/jbc.m301201200 ◽

2003 ◽

Vol 278 (27) ◽

pp. 24912-24920 ◽

Cited By ~ 34

Author(s):

Koichiro Maeno ◽

Kiyonao Sada ◽

Shinkou Kyo ◽

S. M. Shahjahan Miah ◽

Keiko Kawauchi-Kamata ◽

...

Keyword(s):

Tyrosine Kinase ◽

Protein Tyrosine Kinase ◽

Adaptor Protein ◽

Protein Tyrosine ◽

Src Homology 2 ◽

Src Homology ◽

Potential Ligand

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The Src homology 2 domain–containing inositol 5-phosphatase negatively regulates Fcγ receptor–mediated phagocytosis through immunoreceptor tyrosine-based activation motif–bearing phagocytic receptors

Blood ◽

10.1182/blood-2002-03-0787 ◽

2002 ◽

Vol 100 (9) ◽

pp. 3374-3382 ◽

Cited By ~ 66

Author(s):

Koji Nakamura ◽

Alexander Malykhin ◽

K. Mark Coggeshall

Keyword(s):

B Cells ◽

Molecular Mechanisms ◽

Calcium Influx ◽

Dominant Negative ◽

Src Homology 2 ◽

Dominant Negative Form ◽

Igg Receptors ◽

Src Homology ◽

Src Homology 2 Domain ◽

Activation Motif

Abstract Molecular mechanisms by which the Src homology 2 domain-containing inositol 5-phosphatase (SHIP) negatively regulates phagocytosis in macrophages are unclear. We addressed the issue using bone marrow–derived macrophages from FcγR- or SHIP-deficient mice. Phagocytic activities of macrophages from FcγRII(b)−/− and SHIP−/− mice were enhanced to a similar extent, relative to those from wild type. However, calcium influx was only marginally affected in FcγRII(b)−/−, but greatly enhanced in SHIP−/− macrophages. Furthermore, SHIP was phosphorylated on tyrosine residues upon FcγR aggregation even in macrophages from FcγRII(b)−/− mice or upon clustering of a chimeric receptor containing CD8 and the immunoreceptor tyrosine-based activation motif (ITAM)–bearing γ-chain or human-restricted FcγRIIa. These findings indicate that, unlike B cells, SHIP is efficiently phosphorylated in the absence of an immunoreceptor tyrosine-based inhibition motif (ITIM)–bearing receptor. We further demonstrate that SHIP directly bound to phosphorylated peptides derived from FcγRIIa with a high affinity, comparable to that of FcγRII(b). Lastly, FcγRIIa-mediated phagocytosis was significantly enhanced in THP-1 cells overexpressing dominant-negative form of SHIP in the absence of FcγRII(b). These results indicate that SHIP negatively regulates FcγR-mediated phagocytosis through all ITAM-containing IgG receptors using a molecular mechanism distinct from that in B cells.

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B Cell Adaptor Containing Src Homology 2 Domain (Bash) Links B Cell Receptor Signaling to the Activation of Hematopoietic Progenitor Kinase 1

Journal of Experimental Medicine ◽

10.1084/jem.194.4.529 ◽

2001 ◽

Vol 194 (4) ◽

pp. 529-540 ◽

Cited By ~ 48

Author(s):

Sachiyo Tsuji ◽

Mariko Okamoto ◽

Koichi Yamada ◽

Noriaki Okamoto ◽

Ryo Goitsuka ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Tyrosine Phosphorylation ◽

Phosphorylation Site ◽

Sh2 Domain ◽

Hematopoietic Progenitor ◽

Src Homology 2 ◽

Bcr Signaling ◽

Src Homology ◽

Src Homology 2 Domain

The B cell adaptor containing src homology 2 domain (BASH; also termed BLNK or SLP-65), is crucial for B cell antigen receptor (BCR)-mediated activation, proliferation, and differentiation of B cells. BCR-mediated tyrosine-phosphorylation of BASH creates binding sites for signaling effectors such as phospholipase Cγ (PLCγ)2 and Vav, while the function of its COOH-terminal src homology 2 domain is unknown. We have now identified hematopoietic progenitor kinase (HPK)1, a STE20-related serine/threonine kinase, as a protein that inducibly interacts with the BASH SH2 domain. BCR ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation. Furthermore, HPK1 augmented, whereas its kinase-dead mutant inhibited IκB kinase β (IKKβ) activation by BCR engagement. These results reveal a novel BCR signaling pathway leading to the activation of HPK1 and subsequently IKKβ, in which BASH recruits tyrosine-phosphorylated HPK1 into the BCR signaling complex.

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