Increased Numbers of B-1 Cells and Enhanced Responses against TI-2 Antigen in Mice Lacking APS, an Adaptor Molecule Containing PH and SH2 Domains

Iseki, Masanori; Kubo, Chiyomi; Kwon, Sang‐Mo; Yamaguchi, Akiko; Kataoka, Yuki; Yoshida, Nobuaki; Takatsu, Kiyoshi; Takaki, Satoshi

doi:10.1128/mcb.24.6.2243-2250.2004

Cited by 22 publications

(16 citation statements)

References 55 publications

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“…Overexpression of SH2B2 in lymphocytes impairs BCR-induced B cell proliferation and reduces B-1 and B-2 cell number in SH2B2 transgenic mice [150] . Conversely, SH2B2 KO mice have increased B-1 cell number, and SH2B2-deficient B cells display enhanced response to trinitrophenol-Ficoll, a thymus-independent type 2 antigen [149] . SH2B2 appears to be a negative regulator of a subset of immune cells.…”

Section: Sh2b2 Structurementioning

confidence: 99%

“…SH2B2 binds via its SH2 domain to phospho-Tyr 343 of EPO receptors [145] , and it also binds via its phospho-Tyr 618 motif to c-Cbl and recruits c-Cbl E3 ligase to EPO receptors, thereby inhibiting the JAK2/STAT5 pathway in hematopoietic cell lines [145] . SH2B2 is colocalized with B cell antigen receptors (BCRs) and negatively regulates BCR signaling, and it is tyrosyl phosphorylated in response to BCR activation [2,149,150] . SH2B1 and SH2B2 play different roles in regulating immune cell function.…”

Section: Sh2b2 Structurementioning

confidence: 99%

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SH2B1 regulation of energy balance, body weight, and glucose metabolism

Rui

2014

WJD

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The Src homology 2B (SH2B) family members (SH2B1, SH2B2 and SH2B3) are adaptor signaling proteins containing characteristic SH2 and PH domains. SH2B1 (also called SH2-B and PSM) and SH2B2 (also called APS) are able to form homo-or hetero-dimers via their N-terminal dimerization domains. Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins, including Janus kinase 2 (JAK2), TrkA, insulin receptors, insulin-like growth factor-1 receptors, insulin receptor substrate-1 (IRS1), and IRS2. SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/ IRS1/2 signaling complex. SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins. Accordingly, genetic deletion of SH2B1 results in severe leptin resistance, insulin resistance, hyperphagia, obesity, and type 2 diabetes in mice. Neuronspecific overexpression of SH2B1β transgenes protects against diet-induced obesity and insulin resistance. SH2B1 in pancreatic β cells promotes β cell expansion and insulin secretion to counteract insulin resistance in obesity. Moreover, numerous SH2B1 mutations are genetically linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Unlike SH2B1, SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis. The metabolic function of the SH2B family is conserved from insects to humans. Key words: Obesity; Type 2 diabetes; Leptin resistance; Insulin resistance; Glucose intolerance; Hypothalamus; Energy balance; Food intake; Hyperphagia; Nonalcoholic fatty liver disease Core tip: The Src homology 2B (SH2B) family members mediate cell signaling in response to a variety of hormones, cytokines, and growth factors. In the brain, SH2B1 enhances leptin signaling and leptin's antiobesity action. In peripheral tissues, SH2B1 cell-autonomously enhances insulin signaling. In pancreatic islets, SH2B1 is required for compensatory β cell expansion in response to insulin resistance and β cell stress. SH2B1-deficiency results in severe leptin resistance, energy imbalance, obesity, and type 2 diabetes. SH2B1 mutations are linked to leptin resistance, insulin resistance, obesity, and type 2 diabetes in humans. Thus, SH2B1 is a critical metabolic regulator in mammals.Rui L. SH2B1 regulation of energy balance, body weight, and glucose metabolism. World J Diabetes 2014; 5(4): 511-526 Available from:

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Section: Sh2b2 Structurementioning

confidence: 99%

Section: Sh2b2 Structurementioning

confidence: 99%

SH2B1 regulation of energy balance, body weight, and glucose metabolism

Rui

2014

WJD

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“…The response to TI-2 Ags is mainly dependent on B-1 B cells and B cells in the splenic MZ (43)(44)(45). To determine whether these lymphocyte populations are present in reconstituted mice in the absence of IGF-1R expression, we FACS-analyzed peritoneal B-1 and splenic MZ B cells derived from these mice.…”

Section: Decreased T Cell-independent B Cell Response In Igf-1rmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Controls Type 2 T Cell-Independent B Cell Response

Baudler

Baumgartl

Hampel

et al. 2005

The Journal of Immunology

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The IGF-1 receptor (IGF-1R) is expressed on T and B lymphocytes, and the expression of the insulin- and IGF-1-signaling machinery undergoes defined changes throughout lineage differentiation, offering a putative role for IGF-1 in the regulation of immune responses. To study the role of the IGF-1R in lymphocyte differentiation and function in vivo, we have reconstituted immunodeficient RAG2-deficient mice with IGF-1R−/− fetal liver cells. Despite the absence of IGF-1Rs, the development and ex vivo activation of B and T lymphocytes were unaltered in these chimeric mice. By contrast, the humoral immune response to the T cell-independent type 2 Ag 4-hydroxy-3-nitrophenyl acetyl-Ficoll was significantly reduced in mice reconstituted with IGF-1R-deficient fetal liver cells, whereas responses to the T cell-dependent Ag 4-hydroxy-3-nitrophenyl acetyl-chicken globulin were normal. Moreover, in an in vitro model of T cell-independent type 2 responses, IGF-1 promoted Ig production potently upon polyvalent membrane-IgD cross-linking. These data indicate that functional IGF-1R signaling is required for T cell-independent B cell responses in vivo, defining a novel regulatory mechanism for the immune response against bacterial polysaccharides.

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“…12 Mice deficient for members of this family have demonstrated the positive (SH2-B) and negative (Lnk and APS) role of these adaptors in growth factor, cytokine, and antigen-receptor signaling. [13][14][15][16][17][18] In particular, Lnk nullizygous mice show mainly a profound perturbation in hematopoiesis. These animals exhibit splenomegaly together with fibrosis, expansion of hematopoietic stem cells (HSCs), and myeloid and B lymphoid progenitors.…”

Section: Introductionmentioning

confidence: 99%

Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

Simon

Dondi

Chaix

et al. 2008

Blood

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IntroductionMast cells are multifunctional hematopoietic cells, important for both innate and specific immunity. 1 Immature mast cells leave the bone marrow to migrate to target tissues, mostly mucosal and connective tissues, where they undergo terminal differentiation and perform their biologic functions. 2 Stem cell factor (SCF) and its receptor Kit are essential for mast cell development in vivo, as shown by the phenotype of mice with null mutations in the Kit (White Spotting or W) or SCF (Steel or Sl) loci. Indeed, these mice lack tissue mast cells and also exhibit defects in hematopoiesis, pigmentation, and reproduction. 3 In bone marrow mast cells (BMMCs), activation of Kit, a type III receptor tyrosine kinase (RTK), stimulates cellular responses such as proliferation, survival, differentiation, chemotaxis, cell adhesion, and degranulation. 4 Upon SCF binding, the Kit receptor dimerizes, autophosphorylates, and subsequently transphosphorylates specific tyrosines (Y). The resulting phosphotyrosine (pY) residues serve as docking sites for Src homology 2 (SH2) domain-containing proteins, which control intracellular signaling pathways such as all 3 mitogen-activated protein kinases (MAPKs; ERK, p38, and c-jun N-terminal kinase [JNK]), phosphatidylinositol 3-kinase (PI-3K), and Janus kinases (JAK)/signal transducers and activators of transcription (STAT) pathways. 4,5 Recruitment of particular targets is mediated by the ability of SH2 domains to recognize specific pY-containing motifs on the activated receptor. Analyses of individual docking sites on Kit have provided valuable information about the activation of pathways emanating from this receptor. 6 Juxtamembrane Y567 and Y569 are critical recruitment sites for different regulatory signaling molecules. These include activators such as Src family kinases (Fyn and Lyn), Shp-2 phosphatase and Shc adaptor protein, or negative modulators such as Shp-1 phosphatase, Csk-homology kinase (Chk), suppressors of cytokine signaling (SOCS) proteins, and APS adaptor protein. 5,7,8 Mutational and "knock-in" studies on Kit Y567/Y569 have revealed their important role in cell development, proliferation, survival, and migration. 6,9-11 However, the biologic significance of these interactions is still poorly understood.Lnk is a member of the adaptor protein family that includes APS and SH2-B. All 3 members share common protein-protein interaction domains and motifs: a dimerization domain at the aminoterminus, a pleckstrin homology (PH) domain, an SH2 domain, and a conserved tyrosine near the carboxy-terminus. 12 Mice deficient for members of this family have demonstrated the positive (SH2-B) and negative (Lnk and APS) role of these adaptors in growth factor, cytokine, and antigen-receptor signaling. [13][14][15][16][17][18] In particular, Lnk nullizygous mice show mainly a profound perturbation in hematopoiesis. These animals exhibit splenomegaly together with fibrosis, expansion of hematopoietic stem cells (HSCs), and myeloid and B lymphoid progenitors. [17][18][19] Recent ana...

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Increased Numbers of B-1 Cells and Enhanced Responses against TI-2 Antigen in Mice Lacking APS, an Adaptor Molecule Containing PH and SH2 Domains

Abstract: APS (adaptor molecule containing PH and SH2 domains) is an intracellular adaptor protein that forms an

Cited by 22 publications

References 55 publications

SH2B1 regulation of energy balance, body weight, and glucose metabolism

SH2B1 regulation of energy balance, body weight, and glucose metabolism

Insulin-Like Growth Factor-1 Controls Type 2 T Cell-Independent B Cell Response

Lnk adaptor protein down-regulates specific Kit-induced signaling pathways in primary mast cells

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