Leptin stimulates both JAK2-dependent and JAK2-independent signaling pathways
Leptin stimulates both JAK2-dependent and JAK2-independent signaling pathways
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DOI：
10.1074/jbc.m805545200
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发表时间：
2008-10-17
影响因子：
4.8
通讯作者：
Rui, Liangyou
中科院分区：
文献类型：
--
作者：
Jiang, Lin;Li, Zhiqin;Rui, Liangyou
瘦素通过激活长型瘦素受体（LEPRb）来控制体重。Janus激酶2（JAK 2）与LEPRb相关，并响应于瘦素而自磷酸化。JAK 2还磷酸化LEPRb、STAT 3和多种其他下游分子。令人惊讶的是，在这里，我们表明JAK 2是不需要瘦素刺激STAT 3磷酸化。瘦素时间和剂量依赖性地刺激人和小鼠JAK 2-null细胞中STAT 3的酪氨酸磷酸化。瘦素也增加JAK 2-null细胞的活力。过表达的c-Src或Fyn，两个Src家族成员，促进STAT 3磷酸化，而抑制内源性Src家族成员的药理学抑制剂或显性负性Src（K298 M）降低瘦素刺激STAT 3和ERK 1/2磷酸化的能力。瘦素还刺激JAK 2-null细胞中激酶失活的JAK 2（K882 E）的酪氨酸磷酸化。JAK 2（K882 E）的过表达增强了瘦素刺激JAK 2-null细胞中STAT 3磷酸化的能力。LEPRb中的Tyr（1138）是瘦素刺激的STAT 3磷酸化所必需的，而不是JAK 2（K882 E）。这些数据表明，瘦素刺激非JAK 2酪氨酸激酶，包括Src家族成员，其磷酸化JAK 2，STAT 3和LEPRb下游的其他分子。JAK 2通过磷酸化其底物和形成作为支架/衔接蛋白的信号复合物来介导瘦素信号传导。非JAK 2激酶和JAK 2可以协调和协同作用以介导瘦素应答。
Leptin controls body weight by activating the long form of the leptin receptor (LEPRb). Janus kinase 2 (JAK2) is associated with LEPRb and autophosphorylates in response to leptin. JAK2 also phosphorylates LEPRb, STAT3, and multiple other downstream molecules. Surprisingly, here we show that JAK2 is not required for leptin stimulation of STAT3 phosphorylation. Leptin time- and dose-dependently stimulated tyrosine phosphorylation of STAT3 in both human and mouse JAK2-null cells. Leptin also increased the viability of JAK2-null cells. Overexpression of c-Src or Fyn, two Src family members, promoted STAT3 phosphorylation, whereas inhibition of the endogenous Src family members by either pharmacological inhibitors or dominant negative Src(K298M) decreased the ability of leptin to stimulate the phosphorylation of STAT3 and ERK1/2. Leptin also stimulated tyrosine phosphorylation of kinase-inactive JAK2(K882E) in JAK2-null cells. Overexpression of JAK2(K882E) enhanced the ability of leptin to stimulate STAT3 phosphorylation in JAK2-null cells. Tyr(1138) in LEPRb was required for leptin-stimulated phosphorylation of STAT3 but not JAK2(K882E). These data suggest that leptin stimulates non-JAK2 tyrosine kinase(s), including the Src family members, which phosphorylate JAK2, STAT3, and other molecules downstream of LEPRb. JAK2 mediates leptin signaling by both phosphorylating its substrates and forming a signaling complex as a scaffolding/adaptor protein. The non-JAK2 kinase(s) and JAK2 may act coordinately and synergistically to mediate leptin response.