A novel mechanism for JAK2 activation by a G protein-coupled receptor, the CCK2R - Implication of this signaling pathway in pancreatic tumor models
A novel mechanism for JAK2 activation by a G protein-coupled receptor, the CCK2R - Implication of this signaling pathway in pancreatic tumor models
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DOI：
10.1074/jbc.m413309200
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发表时间：
2005-03-18
影响因子：
4.8
通讯作者：
Seva, C
中科院分区：
文献类型：
--
作者：
Ferrand, A;Kowalski-Chauvel, A;Seva, C
到目前为止，很少有G蛋白偶联受体（GPCR）已被证明是连接到Janus激酶（JAK）/STAT途径。因此，我们对GPCR激活该信号通路的机制的了解仍然有限。此外，人们对JAK通路在GPCR的生理或病理生理功能中的作用知之甚少。在这里，我们描述了一种新的JAK激活机制，涉及G α（q）蛋白。事实上，在COS- 7细胞中转染G α（q）的组成型激活突变体（Q209 L）证明G α（q）能够缔合并激活JAK 2。此外，我们发现这种机制主要通过与G（q），CCK 2受体（CCK 2 R）偶联的GPCR来激活JAK 2，并且涉及GPCR中高度保守的序列，NPXXY基序。在表达内源性CCK 2 R的胰腺肿瘤细胞系中，我们证明了JAK 2/STAT 3通路被该受体激活，并且该信号通路参与CCK 2 R的增殖效应。此外，我们在体内表明，Elas-CCK 2小鼠胰腺中的靶向CCK 2 R表达导致JAK 2和STAT 3的激活。这一过程可能有助于胰腺生长的增加以及导致在这些转基因动物中观察到的胰腺肿瘤发展的癌前病变的形成。
To date very few G protein-coupled receptors (GPCRs) have been shown to be connected to the Janus kinase (JAK)/STAT pathway. Thus our understanding of the mechanisms involved in the activation of this signaling pathway by GPCRs remains limited. In addition, little is known about the role of the JAK pathway in the physiological or pathophysiological functions of GPCRs. Here, we described a new mechanism of JAK activation that involves G alpha(q) proteins. Indeed, transfection of a constitutively activated mutant of G alpha(q) (Q209L) in COS- 7 cells demonstrated that G alpha(q) is able to associate and activate JAK2. In addition, we showed that this mechanism is used to activate JAK2 by a GPCR principally coupled to G(q), the CCK2 receptor (CCK2R), and involves a highly conserved sequence in GPCRs, the NPXXY motif. In a pancreatic tumor cell line expressing the endogenous CCK2R, we demonstrated the activation of the JAK2/STAT3 pathway by this receptor and the involvement of this signaling pathway in the proliferative effects of the CCK2R. In addition, we showed in vivo that the targeted CCK2R expression in pancreas of Elas-CCK2 mice leads to the activation of JAK2 and STAT3. This process may contribute to the increase of pancreas growth as well as the formation of preneoplastic lesions leading to pancreatic tumor development observed in these transgenic animals.