SH2-B, a Membrane-associated Adapter, Is Phosphorylated on Multiple Serines/Threonines in Response to Nerve Growth Factor by Kinases within the MEK/ERK Cascade

Rui, Liangyou; Herrington, James; Carter‐Su, Christin

doi:10.1074/jbc.274.37.26485

Cited by 41 publications

(49 citation statements)

References 67 publications

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“…Alternatively, SH2-B␤ might take one or more of the proteins required for these events to the wrong subcellular location or affect the ability of FKHR to be phosphorylated on the casein kinase I phosphorylation sites Ser 322 and Ser 325 . Any of these scenarios could occur as a consequence of SH2-B␤(R555E) not binding to TrkA (or other neurotrophic receptor tyrosine kinases) and/or not being phosphorylated on tyrosines, serines, or threonines as a consequence of not binding to activated TrkA (57,75). However, the fact that overexpression of SH2-B␤ causes FKHR to shift to the cytoplasm in the absence of NGF suggests that modification of SH2-B␤ by TrkA is not necessary for SH2-B␤ to affect the subcellular distribution of FKHR.…”

Section: Discussionmentioning

confidence: 99%

SH2-B Is a Positive Regulator of Nerve Growth Factor-mediated Activation of the Akt/Forkhead Pathway in PC12 Cells

Wang

Chen

Maures

et al. 2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

SH2-B Is a Positive Regulator of Nerve Growth Factor-mediated Activation of the Akt/Forkhead Pathway in PC12 Cells

Wang

Chen

Maures

et al. 2004

Journal of Biological Chemistry

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“…In the PDGFR beta signaling pathway PSM appears not to control the PI3K or MAP kinase signaling cascades since cell-permeable PSM SH2 domain peptides which inhibit PSM-PDGFR beta association in vitro (Figure 1) and mitogenesis in vivo (Figure 4) did not aect PI3K or MAP kinase activity (data not shown). The signaling pathway employed in the mitogenic responses to PSM has not been identi®ed yet which will be a premier focus of future studies (Rui et al, 1999b).…”

Section: Discussionmentioning

confidence: 99%

“…An association of PSM/SH2-B was established with the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) that depends on receptor activation and was mapped to phospho-tyrosine sites which are conserved between the insulin and IGF-I receptors (Wang and Riedel, 1998). For SH2-B beta an association was described with PDGFR in response to PDGF activation which stimulated SH2-B beta phosphorylation on tyrosine, serine, and threonine (Rui and Carter-Su, 1998) which was also reported in response to nerve growth factor by kinases within the MEK/ERK cascade (Rui et al, 1999b). In response to insulin, tyrosine phosphorylation had originally not been observed for any form of PSM (Rui et al, 1997;Wang and Riedel, 1998) but has more recently been reported including a role as a substrate of IR (Kotani et al, 1998;Ahmed et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis

Riedel

Yousaf

Zhao³

et al. 2000

Oncogene

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PSM/SH2-B has been described as a cellular partner of the FceRI receptor, insulin receptor (IR), insulin-like growth factor-I (IGF-I) receptor (IGF-IR), and nerve growth factor receptor (TrkA). A function has been proposed in neuronal dierentiation and development but its role in other signaling pathways is still unclear. To further elucidate the physiologic role of PSM we have identi®ed additional mitogenic receptor tyrosine kinases as putative PSM partners including platelet-derived growth factor (PDGF) receptor (PDGFR) beta, hepatocyte growth factor receptor (Met), and ®broblast growth factor receptor. We have mapped Y740 as a site of PDGFR beta that is involved in the association with PSM. We have further investigated the putative role of PSM in mitogenesis with three independent experimental strategies and found that all consistently suggested a role as a positive, stimulatory signaling adapter in normal NIH3T3 and baby hamster kidney ®broblasts. (1) PSM expression from cDNA using an ecdysone-regulated transient expression system stimulated PDGF-BB-, IGF-I-, and insulin-but not EGF-induced DNA synthesis in an ecdysone dose-responsive fashion; (2) Microinjection of the (dominant negative) PSM SH2 domain interfered with PDGF-BB-and insulin-induced DNA synthesis; and (3) A peptide mimetic of the PSM Prorich putative SH3 domain-binding region interfered with PDGF-BB-, IGF-I-, and insulin-but not with EGFinduced DNA synthesis in NIH3T3 ®broblasts. This experiment was based on cell-permeable fusion peptides with the Drosophila antennapedia homeodomain which eectively traverse the plasma membrane of cultured cells. These experimental strategies independently suggest that PSM functions as a positive, stimulatory, mitogenic signaling mediator in PDGF-BB, IGF-I, and insulin but not in EGF action. This function appears to involve the PSM SH2 domain as well as the Pro-rich putative SH3 domain binding region. Our ®ndings support the model that PSM participates as an adapter in various mitogenic signaling mechanisms by linking an activated (receptor) phospho-tyrosine to the SH3 domain of an unknown cellular partner. Oncogene (2000) 19, 39 ± 50.

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“…Therefore, the NLS, NES, and SH2 domain all are involved in the regulation of SH2B1 trafficking between the cytoplasmic and nuclear compartments. SH2B1 is also translocated to the plasma membrane [21] . A N-terminal polybasic region (S 145 KPKLKKRF), which overlaps the NLS, is required, but not sufficient, for SH2B1β translocation to the plasma membrane [22] .…”

Section: Metabolic Function Of Sh2b1mentioning

confidence: 99%

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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SH2-B, a Membrane-associated Adapter, Is Phosphorylated on Multiple Serines/Threonines in Response to Nerve Growth Factor by Kinases within the MEK/ERK Cascade

Cited by 41 publications

References 67 publications

SH2-B Is a Positive Regulator of Nerve Growth Factor-mediated Activation of the Akt/Forkhead Pathway in PC12 Cells

SH2-B Is a Positive Regulator of Nerve Growth Factor-mediated Activation of the Akt/Forkhead Pathway in PC12 Cells

PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis

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

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