Identification of SH2-Bβ as a Substrate of the Tyrosine Kinase JAK2 Involved in Growth Hormone Signaling

Rui, Liangyou; Mathews, Lawrence S.; Hotta, Kikuko; Gustafson, Thomas A.; Carter‐Su, Christin

doi:10.1128/mcb.17.11.6633

Cited by 163 publications

(207 citation statements)

References 31 publications

(24 reference statements)

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“…Solubilized proteins were separated by SDS-PAGE. Proteins in the gel were transferred to a nitrocellulose membrane and detected by immunoblotting with desired antibodies and enhanced chemiluminescence (63). For quantification, immunoblots with signals in the linear range were scanned and the resulting images were analyzed using multi-analyst image software from Bio-Rad (Figs.…”

Section: Methodsmentioning

confidence: 99%

“…cDNAs encoding GFPtagged wild-type SH2-B␤ and SH2-B␤(R555E) have been described previously (57). Anti-SH2-B␤ antibody (␣SH2-B␤) was prepared as described previously (63) and used at a dilution of 1:15,000 for Western blotting. Antibodies that recognize the following proteins were used for Western blotting at a dilution of 1:1000: phospho-Akt (Ser 473 ) (␣pAkt-Ser 473 ) (Cell Signaling, 9276), Akt (␣Akt) (Cell Signaling, 9272), FKHRL1 (␣FKHRL1) (Upstate Biotechnology, 06-951), phospho-GSK-3(Ser 21/9 ) (␣pGSK-3) (Cell Signaling, 9331S), and phospho-GSK-3(Y279/ Y216) (used to detect total GSK-3) (␣GSK-3) (Upstate Biotechnology, 05-413).…”

Section: Methodsmentioning

confidence: 99%

“…Four SH2-B isoforms (␣, ␤, ␥, ␦) have now been identified; they differ in their C termini downstream of the SH2 domain (63)(64)(65)(66) (Fig. 1).…”

mentioning

confidence: 99%

“…SH2-B was identified as a binding protein of the receptor for NGF (TrkA) (57,58), as well as of the receptors for insulin (59), platelet-derived growth factor (60), fibroblast growth factor (61), insulin-like growth factor-1 (62), hepatocyte growth factor (61), the cytokine receptor-associated tyrosine kinase JAK2 (63), and the R1 Fc⑀R1 receptor (64). Four SH2-B isoforms (␣, ␤, ␥, ␦) have now been identified; they differ in their C termini downstream of the SH2 domain (63)(64)(65)(66) (Fig.…”

mentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Four SH2-B isoforms (␣, ␤, ␥, ␦) have now been identified; they differ in their C termini downstream of the SH2 domain (63)(64)(65)(66) (Fig. 1).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…SH2-B, a recently described adapter protein containing SH2 and pleckstrin homology (PH) domains (27,28), has been shown to be required for NGF-induced neuronal differentiation of PC12 cells (16) and implicated in NGF-mediated axonal growth and survival of primary sympathetic neurons (15). NGF stimulates association of SH2-B with TrkA in PC12 cells (16) as well as in primary sympathetic neurons (15).…”

mentioning

confidence: 99%

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

Herrington

Carter‐Su

1999

Journal of Biological Chemistry

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SH2-B has been shown to be required for nerve growth factor (NGF)-mediated neuronal differentiation and survival, associate with NGF receptor TrkA, and be tyrosylphosphorylated in response to NGF. In this work, we examined whether NGF stimulates phosphorylation of SH2-B on serines/threonines. NGF promotes a dramatic upward shift in mobility of SH2-B, resulting in multiple forms that cannot be attributed to tyrosyl phosphorylation. Treatment of SH2-B with protein phosphatase 2A, a serine/threonine phosphatase, reduces the many forms to two. PD98059, a MEK inhibitor, dramatically inhibits NGF-promoted phosphorylation of SH2-B on serines/ threonines, whereas depletion of 4␤-phorbol 12-myristate 13-acetate-sensitive protein kinase Cs does not. ERKs 1 and 2 phosphorylate SH2-B␤ primarily on Ser-96 in vitro. However, NGF still stimulates serine/threonine phosphorylation of SH2-B␤(S96A). SH2-B␤(S96A), like wildtype SH2-B␤, enhances NGF-induced neurite outgrowth. In contrast, SH2-B␤(R555E) containing a defective SH2 domain blocks NGF-induced neurite outgrowth and displays greatly reduced phosphorylation on serines/threonines in response to NGF. SH2-B␤(R555E), like wild-type SH2-B␤, associates with the plasma membrane, suggesting that the dominant negative effect of SH2-B␤(R555E) cannot be explained by an abnormal subcellular distribution. In summary, NGF stimulates phosphorylation of SH2-B on serines/ threonines by kinases downstream of MEK, which may be important for NGF-mediated neuronal differentiation and survival.

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SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit

Li,

Kim,

Jiang

et al. 2024

Advanced Science

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SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction‐associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron‐specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1‐null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1‐expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic‐onset or adult‐onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN‐projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN‐projecting PVHSH2B1 neurons protects against diet‐induced obesity. SH2B1 binds to TrkB and enhances brain‐derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling.

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Identification of SH2-Bβ as a Substrate of the Tyrosine Kinase JAK2 Involved in Growth Hormone Signaling

Cited by 163 publications

References 31 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

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

SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit

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