A Novel Mechanism for JAK2 Activation by a G Protein-coupled Receptor, the CCK2R

Ferrand, Audrey; Kowalski‐Chauvel, Aline; Castro, Bertrand; Escrieut, Chantal; Mathieu, Anne; Portolan, Ghislaine; Pradayrol, Lucien; Fourmy, Daniel; Dufresne, Marlène; Seva, Catherine

doi:10.1074/jbc.m413309200

Cited by 65 publications

(37 citation statements)

References 22 publications

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“…Another possibility, however, is that gastrin and LIF act via a common signal transduction pathway leading to endocrine cell differentiation of the progenitors. Indeed, it has recently been shown that the CCK2 gastrin receptor in pancreatic cells can activate the JAK2/STAT3 pathway [44]. This pathway is the one which is also activated by LIFR/gp130 signalling [22].…”

Section: Discussionmentioning

confidence: 99%

Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas

2005

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Aims/hypothesis: It was recently reported that culturing adult exocrine cells in the presence of epidermal growth factor and leukaemia inhibitory factor (LIF) resulted in their transdifferentiation into endocrine beta cells. The aim of this study was to examine the expression and function of LIF in the pancreas. Materials and methods: We studied the expression of LIF and its receptor components, LIF-receptor-β and gp130, by immunohistochemistry, western blotting and RT-PCR in normal rat pancreas, pancreas with duct ligation-induced islet neogenesis, and in pancreatic cell cultures. Isolated duct fragments were cultured in the presence of LIF and a janus kinase 2 (JAK2) inhibitor. Results: LIF was detected by immunohistochemistry, western blot and RT-PCR in the ducts of the normal pancreas. Both LIF-receptor-β and gp130 were detected by RT-PCR in the pancreas. Immunostaining revealed gp130 exclusively in the ducts and centro-acinar cells. After duct ligation-induced tissue injury, upregulation of LIF and its receptor occurred in rat pancreas. Metaplastic exocrine cells also started to express LIF and this was increased after alloxan treatment. Signalling via LIF-receptor-β/gp130 involves the JAK/signal transducer and activator of transcription (STAT) pathway. LIF induced increased activation of STAT3 in pancreatic cells. In isolated duct fragments, addition of LIF resulted in a significant increase in duct cell proliferation, while a specific inhibitor of the JAK/STAT signalling pathway inhibited proliferation. Conclusion/interpretation: Our observations show that LIF and its receptor are expressed in cells from pancreatic ducts. The cytokine plays a role in pancreatic physiology, controls duct cell proliferation and is involved in repair processes following pancreatic injury.

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Section: Discussionmentioning

confidence: 99%

Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas

2005

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“…This pathway is activated by a diversity of receptors, including receptor tyrosine kinases [38,45,51] and Gprotein-coupled receptors [11,33]. Upon activation of JAK, STAT proteins dimerize and translocate to the nucleus, where they mediate gene transcription (reviewed by Sandberg et al [36]).…”

Section: Introductionmentioning

confidence: 99%

Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

et al. 2008

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Objective-To evaluate the significance of the JAK-STAT pathway in insulin-induced cardioprotection from reperfusion injury. Correspondence to: Britt N. Fuglesteg, brittf@fagmed.uit.no Methods-In isolated perfused rat hearts subjected to insulin therapy (0.3 mU/ml) ± AG490 (5 μM, JAK-STAT inhibitor), the phosphorylation state of STAT3 and Akt was determined after 15 min of reperfusion. Infarct size was measured after 120 min of reperfusion. Isolated cardiac myocytes from wild type (WT) and cardiac specific STAT3 deficient mice were treated with insulin at reoxygenation following simulated ischemia (SI, 26 h). Cell viability was measured after 120 min of reoxygenation following SI, whereas phosphorylation state of Akt was measured after 15 min of reoxygenation following SI.Results-Insulin given at reperfusion led to phosphorylation of STAT3 and Akt both of which were inhibited by AG490. AG490 also blocked the insulin-dependent decrease in infarct size, supporting a role for JAK-STAT in cardioprotection. In addition, insulin protection from SI was blocked in myocytes from the STAT3 deficient mice, or in WT mice treated with AG490. Furthermore, insulin failed to phosphorylate Akt in the STAT3 deficient cardiomyocytes.Conclusion-Insulin-induced cardioprotection at reperfusion occurs through activation of STAT3. Inhibiting STAT3 by AG490, or STAT3 depletion in cardiac myocytes affects activation of Akt, suggesting close interaction between STAT3 and Akt in the cardioprotective signalling pathway activated by insulin treatment at reperfusion.

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“…Western blot analysis on isolated acinar cells or Panc-1 cells Western blot analyses were performed on (i) dispersed acini from mice pancreas prepared as previously described (Ferrand et al, 2005) or on (ii) lysates or immunoprecipitates from Panc-1 cells stimulated or not stimulated with gastrin. Fractions, containing identical levels of proteins, were separated by SDS-PAGE and analysed by Western blot with the indicated antibodies as described previously (KowalskiChauvel et al, 1996).…”

Section: 'Cancer Super Array'mentioning

confidence: 99%

“…Immunohistochemistry was performed, as previously described (Ferrand et al, 2005) using anti-b1-integrin antibodies (Chemicon, Temecula, CA, USA). Sections were incubated with the appropriate secondary and tertiary peroxidase-labelled antisera (DAKO, Glostrup, Denmark) at room temperature, exposed to a solution of diaminobenzidine.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

“…They include mitogen activated protein-kinases (Todisco et al, 1997;Daulhac et al, 1999b), the phosphatidylinositol 3-kinase and the JAK2/STAT3 pathway (Kowalski-Chauvel et al, 1996;Ferrand et al, 2004Ferrand et al, , 2005. In addition, Src family tyrosine kinases and p125FAK have also been shown to play a crucial role in these gastrin biological effects (Daulhac et al, 1999a, b).…”

Section: Introductionmentioning

confidence: 99%

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Cholecystokinin-2 receptor modulates cell adhesion through β1-integrin in human pancreatic cancer cells

et al. 2006

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Several lines of evidence suggest that gastrin and the CCK-2 receptor (CCK2R) could contribute to pancreatic carcinogenesis by modulating processes such as proliferation, cell adhesion or migration. In the current study, we used a 'cancer gene array' and identified b1-integrin subunit as a new gastrin-regulated gene in human pancreatic cancer cells. We also demonstrated that Src family kinases and the phosphatidylinositol-3-kinase (PI-3-kinase) pathway play a crucial role in the expression of b1-integrin induced by gastrin. Our results also showed that gastrin modulates cell-substrate adhesion via b1-integrin. Indeed, using blocking anti-b1-integrin monoclonal antibodies, we completely reversed the increase in cellsubstrate adhesion induced by gastrin. In addition, we observed that in response to gastrin, b1-integrin is tyrosine phosphorylated by Src family kinases and associates with paxillin, a scaffold protein involved in focal adhesion and integrin signalling. This mechanism might be involved in gastrin-induced cell adhesion. Moreover, we showed in vivo that targeted CCK2R expression in the pancreas of Elas-CCK2 mice leads to the overexpression of b1-integrin. This process may contribute to pancreatic tumour development observed in these transgenic animals.

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A Novel Mechanism for JAK2 Activation by a G Protein-coupled Receptor, the CCK2R

Cited by 65 publications

References 22 publications

Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas

Expression and function of leukaemia inhibitory factor and its receptor in normal and regenerating rat pancreas

Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

Cholecystokinin-2 receptor modulates cell adhesion through β1-integrin in human pancreatic cancer cells

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