Growth hormone signaling pathways.
Growth hormone signaling pathways.
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DOI：
10.1016/j.ghir.2015.09.002
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Argetsinger LS
中科院分区：
文献类型：
--
作者：
Carter-Su C;Schwartz J;Argetsinger LS
20多年前，我们的实验室发现生长激素（GH）信号通过GH受体相关的酪氨酸激酶JAK 2。我们发现GH与其膜结合受体的结合增强了JAK 2与GHR的结合，激活JAK 2，并刺激JAK 2和GHR的酪氨酰磷酸化。活化的JAK 2/GHR复合物募集多种信号蛋白，从而启动多种信号通路和细胞反应。这些蛋白质和途径包括：1）参与多种基因表达的Stat转录因子，包括编码胰岛素样生长因子1的基因; 2）导致grb 2-SOS-Ras-Raf-MEK-ERK 1，2途径活化的Shc衔接蛋白; 3）参与磷脂酰肌醇-3-激酶和Akt途径的胰岛素受体底物蛋白; 4）信号调节蛋白α，一种跨膜支架蛋白，其募集包括酪氨酸磷酸酶SHP 2在内的蛋白质;和5）SH 2B 1，一种支架蛋白，其可以激活JAK 2并增强肌动蛋白细胞骨架的GH调节。我们最近的工作集中在SH 2B 1的功能上。我们已经表明，SH 2B 1 β被募集到JAK 2并被JAK 2磷酸化以响应GH。SH 2B 1定位于质膜、细胞质和局灶性粘连;它还循环通过细胞核。SH 2B 1调节肌动蛋白细胞骨架并促进RAW 264.7巨噬细胞的GH依赖性运动。SH 2B 1突变已在表现出严重早发性儿童肥胖和胰岛素抵抗的人类中发现。这些突变损害SH 2B 1增强GH诱导的巨噬细胞运动。由于SH 2B 1是普遍表达的，也被招募到各种受体酪氨酸激酶，我们的研究结果提高了SH 2B 1对各种细胞类型（包括神经元）中肌动蛋白细胞骨架的影响可能在调节体重中发挥作用。
Over 20 years ago, our laboratory showed that growth hormone (GH) signals through the GH receptor-associated tyrosine kinase JAK2. We showed that GH binding to its membrane-bound receptor enhances binding of JAK2 to the GHR, activates JAK2, and stimulates tyrosyl phosphorylation of both JAK2 and GHR. The activated JAK2/GHR complex recruits a variety of signaling proteins, thereby initiating multiple signaling pathways and cellular responses. These proteins and pathways include: 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin-like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein α, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton. Our recent work has focused on the function of SH2B1. We have shown that SH2B1β is recruited to and phosphorylated by JAK2 in response to GH. SH2B1 localizes to the plasma membrane, cytoplasm and focal adhesions; it also cycles through the nucleus. SH2B1 regulates the actin cytoskeleton and promotes GH-dependent motility of RAW264.7 macrophages. Mutations in SH2B1 have been found in humans exhibiting severe early-onset childhood obesity and insulin resistance. These mutations impair SH2B1 enhancement of GH-induced macrophage motility. As SH2B1 is expressed ubiquitously and is also recruited to a variety of receptor tyrosine kinases, our results raise the possibility that effects of SH2B1 on the actin cytoskeleton in various cell types, including neurons, may play a role in regulating body weight.
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影响因子：
5.3
作者：
CHEATHAM, B;VLAHOS, CJ;KAHN, CR
通讯作者：
KAHN, CR
影响因子：
4
作者：
Cui, Tracy Xiao;Kwok, Roland;Schwartz, Jessica
通讯作者：
Schwartz, Jessica
影响因子：
4.8
作者：
Diakonova, M;Gunter, DR;Carter-Su, C
通讯作者：
Carter-Su, C
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.89.16.7840
发表时间：
1992-08-15
影响因子：
11.1
作者：
FU, XY;SCHINDLER, C;DARNELL, JE
通讯作者：
DARNELL, JE