Blog
About

0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

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

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32), is frequently overexpressed in earlt 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 DARPP-32 on activation of IGF1R and STAT3 signaling and gastric tumorigenesis. DARPP-32 enhanced phosphorylation of IGF1R (Y1135), a step that was critical for STAT3 phosphorylation at Y705, nuclear localization, and transcription activation. By using proximity ligation and co-immunoprecipitation assays, we found that IGF1R and DARPP-32 co-existed in the same protein complex. Binding of DARPP-32 to IGF1R promoted IGF1R phosphorylation with subsequent activation of downstream SRC and STAT3. Analysis of gastric tissues from the TFF1 knockout (KO) mouse model of gastric neoplasia, demonstrated phosphorylation of STAT3 in the early stages of gastric tumorigenesis. By crossing the TFF1 KO mice with DARPP-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 STAT3. In addition, the TFF1 KO/DP KO mice had significant delay in developing neoplastic gastric lesions. Analysis of human gastric cancer tissue microarrays, showed high levels of DARPP-32 and positive immunostaining for nuclear STAT3 in cancer tissues, as compared to non-cancer histologically normal tissues. In summary, the presence of a signaling axis mediated by DARPP-32–IGF1R is a critical step in gastric tumorigenesis, playing an important role in activation of STAT3.

          Related collections

          Most cited references 29

          • Record: found
          • Abstract: found
          • Article: not found

          Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling.

          The successful treatment of certain autoimmune conditions with the humanized anti-IL-6 receptor (IL-6R) antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 (gp130). In this Review, we explore how gp130 signaling controls disease progression and examine why IL-6 has a special role among these cytokines as an inflammatory regulator. Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            DARPP-32: regulator of the efficacy of dopaminergic neurotransmission.

            Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer.

              The insulin-like growth factor (IGF) axis mediates growth, differentiation and developmental processes, and is also involved in control of metabolic activities. Deregulation of IGF axis expression and action is linked to a number of pathologies, ranging from metabolic disorders to growth deficits and cancer development. Activation of the IGF signaling pathway is a crucial prerequisite for malignant transformation. In addition, overexpression of the IGF-1 receptor (IGF-1R) constitutes a typical hallmark of most types of cancer. A series of tumor suppressors have been identified whose mechanisms of action involve transcriptional suppression of the IGF-1R gene. These tumor suppressors include the p53/p63/p73 family, breast cancer gene-1, von-Hippel Lindau protein, Wilms' tumor-1 and others. Comprehensive analyses have identified a complex bidirectional interplay between the IGF and tumor-suppressor signaling pathways. These interactions are of major importance in terms of cancer development and may also predict responsiveness to IGF-1R-targeted therapies. Furthermore, the insulin/IGF system has a pivotal role in the regulation of cancer cell metabolism. Deregulation of IGF axis components by mutated tumor-suppressor proteins may lead to metabolic perturbations, with ensuing pathological consequences.
                Bookmark

                Author and article information

                Contributors
                Journal
                8711562
                6325
                Oncogene
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                4 March 2019
                24 June 2019
                July 2019
                24 December 2019
                : 38
                : 29
                : 5805-5816
                Affiliations
                [1 ]Department of Surgery, Miller School of Medicine, University of Miami, Miami, Florida, USA.
                [2 ]Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA.
                [3 ]Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida, USA.
                [4 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
                [5 ]Department of Pathology, and Vanderbilt University Medical Center, Nashville, Tennessee, USA
                [6 ]Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
                Author notes
                [* ]Corresponding author Wael El-Rifai, M.D., Ph.D., Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL 33136-1015, wxe45@ 123456miami.edu
                Article
                NIHMS1522657
                10.1038/s41388-019-0843-1
                6639157
                31235784

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Categories
                Article

                Oncology & Radiotherapy

                cancer, human, mouse, organoids, darpp-32

                Comments

                Comment on this article