APS, an adaptor molecule containing PH and SH2 domains, has a negative regulatory role in B cell proliferation

Iseki, Masanori; Kubo-Akashi, Chiyomi; Kwon, Sang‐Mo; Yamaguchi, Akiko; Takatsu, Kiyoshi; Takaki, Satoshi

doi:10.1016/j.bbrc.2005.03.073

Cited by 13 publications

(10 citation statements)

References 39 publications

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“…It is likely that APS negatively regulates leptin and/or insulin sensitivity under certain conditions, including absence or reduced expression of SH2-B. APS has been shown to negatively regulate cell signaling which promotes B cell proliferation (34). However, SH2-B may exert a dominant stimulatory effect over an APS inhibitory effect on leptin and insulin sensitivity; therefore, deletion of APS alone does not alter leptin and insulin sensitivity, adiposity and glucose metabolism in the presence of SH2-B.…”

Section: Discussionmentioning

confidence: 99%

Differential Role of SH2-B and APS in Regulating Energy and Glucose Homeostasis

Ren

Iseki

et al. 2006

Endocrinology

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SH2-B and APS, two members of a pleckstrin homology and SH2 domain-containing adaptor family, promote both insulin and leptin signaling in a similar fashion in cultured cells. In addition, APS mediates insulin-stimulated activation of the c-Cbl/CAP/TC10 pathway in cultured adipocytes. Here we characterized genetically modified mice lacking SH2-B, APS, or both to determine the physiological roles of these two proteins in animals. Disruption of the SH2-B gene resulted in obesity, hyperglycemia, hyperinsulinemia, and glucose intolerance. Conversely, deletion of the APS gene did not alter adiposity, energy balance, and glucose metabolism. Energy intake, energy expenditure, fat content, body weight, and plasma insulin, leptin, glucose, and lipid levels were similar between APS(-/-) and WT littermates fed either normal chow or a high-fat diet. Moreover, deletion of APS failed to alter insulin and glucose tolerance. APS(-/-)/SH2-B(-/-) double knockout mice also developed energy imbalance, obesity, hyperleptinemia, hyperinsulinemia, hyperglycemia, and glucose intolerance; however, plasma leptin and insulin levels were significantly lower in APS(-/-)/SH2-B(-/-) than in SH2-B(-/-) mice. These results suggest that SH2-B, but not APS, is a key positive regulator of energy and glucose metabolism in mice.

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Section: Discussionmentioning

confidence: 99%

Differential Role of SH2-B and APS in Regulating Energy and Glucose Homeostasis

Ren

Iseki

et al. 2006

Endocrinology

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“…In contrast, SH2B2-deficient mast cells display augmented degradulation after crosslinking FcRI [151] . SH2B2 is expressed in B cells but not in T cells [150] . 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] .…”

Section: Sh2b2 Structurementioning

confidence: 96%

“…SH2B2 is expressed in B cells but not in T cells [150] . 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] .…”

Section: Sh2b2 Structurementioning

confidence: 96%

“…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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“…Ablation of APS in mice caused an increase in B-1 cell number and an enhanced humoral immune response against a thymus-independent type 2 antigen, suggesting a role for APS in mature B cell proliferation (Iseki et al, 2004). Accordingly, APS transgenic mice showed reduced numbers of peritoneal B-1 and splenic B cells and impaired BCR-induced proliferation of mature B cells (Iseki et al, 2005). In these cells, APS co-localized with pre-activated capped BCR complexes and filamentous actin, indicating a negative regulatory role for APS in BCR signalling and actin reorganization.…”

Section: Signalling Pathways In Haematopoietic Cellsmentioning

confidence: 99%

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

Velázquez¹

2012

Hematology - Science and Practice

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APS, an adaptor molecule containing PH and SH2 domains, has a negative regulatory role in B cell proliferation

Cited by 13 publications

References 39 publications

Differential Role of SH2-B and APS in Regulating Energy and Glucose Homeostasis

Differential Role of SH2-B and APS in Regulating Energy and Glucose Homeostasis

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

Negative Regulation of Haematopoiesis: Role of Inhibitory Adaptors

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