Activation of IGF1R by DARPP-32 promotes STAT3 signaling in gastric cancer cells.

Dopamine and cAMP-regulated phosphoprotein, Mr 32000 is frequently overexpressed in early stages of gastric cancers. We utilized in vitro assays, 3D gastric gland organoid cultures, mouse models, and human tissue samples to investigate the biological and molecular impact of on activation of IGF1R and signaling and gastric tumorigenesis. Dduanyu37P-32 enhanced phosphorylation of IGF1R (Y1135), a step that was critical for duanyu18133 phosphorylation at Y705, nuclear localization, and transcription activation. By using proximity ligation and co-immunoprecipitation assays, we found that IGF1R and Dduanyu37P-32 co-existed in the same protein complex. Binding of Dduanyu37P-32 to IGF1R promoted IGF1R phosphorylation with subsequent activation of downstream SRC and Analysis of gastric tissues from the TFF1 knockout (KO) mouse model of gastric neoplasia, demonstrated phosphorylation of duanyu18133 in the early stages of gastric tumorigenesis. By crossing the TFF1 KO mice with Dduanyu37P-32 (DP) knockout (KO) mice, that have normal stomach, we obtained double knockout (TFF1 KO/DP KO). The gastric mucosa from the double KO mice did not show phosphorylation of IGF1R or duanyu18133. In addition, the TFF1 KO/DP KO mice had a significant delay in developing neoplastic gastric lesions. Analysis of human gastric cancer tissue microarrays, showed high levels of Dduanyu37P-32 and positive immunostaining for nuclear duanyu18133 in cancer tissues, as compared to non-cancer histologically normal tissues. In summary, the signaling axis plays a key role in regulating the duanyu18133 signaling, a critical step in gastric tumorigenesis.

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