The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway has been implicated in cell transformation and proliferation. Besides aberrant cell proliferation, loss of cell-cell adhesion during epithelial-mesenchymal transition (EMT) is an important event which occurs during development of epithelial cancers. However, the role of JAK-dependent pathways in this process is not known. We analyzed the involvement of these pathways in the regulation of E-cadherin-dependent cell-cell adhesion by gastrin, a mitogenic factor for gastrointestinal (GI) tract. We identified JAK2/STAT3 as a new pathway in gastrin signaling. We demonstrated that JAK2 functions as an upstream mediator of the phosphatidylinositol 3 (PI 3)-kinase activity in gastrin signaling. Indeed, we observed a coprecipitation of both kinases and an inhibition of gastrin-induced PI 3-kinase activation when JAK2 activity is blocked. We also demonstrated that loss of cell-cell adhesion and the increase in cell motility induced by gastrin required the activation of JAK2 and the PI 3-kinase. Indeed, the modifications in localization of adherens junctions proteins and the migration, observed in gastrin-stimulated cells, were reversed by inhibition of both kinases. These results described the involvement of JAK2 in the modulation of cell-cell adhesion in epithelial cells. They support a possible role of JAK2 in the epithelial-mesenchymal transition which occurs during malignant development. (C) 2004 Elsevier Inc. All rights reserved.
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Burke, WM
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Jin, XH
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Jin, XH
;
Lin, HJ
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Lin, HJ
;
Huang, M
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Huang, M
;
Liu, R
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Liu, R
;
Reynolds, RK
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Reynolds, RK
;
Lin, JY
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Burke, WM
;
Jin, XH
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Jin, XH
;
Lin, HJ
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Lin, HJ
;
Huang, M
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Huang, M
;
Liu, R
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Liu, R
;
Reynolds, RK
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA
Reynolds, RK
;
Lin, JY
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Univ Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USAUniv Michigan, Ctr Comprehens Canc, Div Gynecol Oncol, Dept Obstet & Gynecol, Ann Arbor, MI 48109 USA