The Journal of biological chemistry, 2003-10, Vol.278 (41), p.39356-39371
2003
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- sst2 Somatostatin Receptor Inhibits Cell Proliferation through Ras-, Rap1-, and B-Raf-dependent ERK2 Activation
- Ist Teil von
- The Journal of biological chemistry, 2003-10, Vol.278 (41), p.39356-39371
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2003
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- The G protein-coupled sst2 somatostatin receptor is a critical negative regulator of cell proliferation. sstII prevents growth factor-induced cell proliferation through activation of the tyrosine phosphatase SHP-1 leading to induction of the cyclin-dependent kinase inhibitor p27Kip1. Here, we investigate the signaling molecules linking sst2 to p27Kip1. In Chinese hamster ovary-DG-44 cells stably expressing sst2 (CHO/sst2), the somatostatin analogue RC-160 transiently stimulates ERK2 activity and potentiates insulin-stimulated ERK2 activity. RC-160 also stimulates ERK2 activity in pancreatic acini isolated from normal mice, which endogenously express sst2, but has no effect in pancreatic acini derived from sst2 knock-out mice. RC-160-induced p27Kip1 up-regulation and inhibition of insulin-dependent cell proliferation are both prevented by pretreatment of CHO/sst2 cells with the MEK1/2 inhibitor PD98059. In addition, using dominant negative mutants, we show that sst2-mediated ERK2 stimulation is dependent on the pertussis toxin-sensitive Gi/o protein, the tyrosine kinase Src, both small G proteins Ras and Rap1, and the MEK kinase B-Raf but is independent of Raf-1. Phosphatidylinositol 3-kinase (PI3K) and both tyrosine phosphatases, SHP-1 and SHP-2, are required upstream of Ras and Rap1. Taken together, our results identify a novel mechanism whereby a Gi/o protein-coupled receptor inhibits cell proliferation by stimulating ERK signaling via a SHP-1-SHP-2-PI3K/Ras-Rap1/B-Raf/MEK pathway.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9258eISSN: 1083-351XDOI: 10.1074/jbc.M304524200Titel-ID: cdi_proquest_miscellaneous_18879985
- Format
- –
- Schlagworte
- Animals, Cell Cycle Proteins - metabolism, Cell Division - drug effects, Cell Division - physiology, CHO Cells, Cricetinae, Cyclin-Dependent Kinase Inhibitor p27, Enzyme Activation - drug effects, Insulin - pharmacology, Intracellular Signaling Peptides and Proteins, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 1 - metabolism, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases - metabolism, Models, Biological, Pancreas - drug effects, Pancreas - metabolism, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases - metabolism, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-raf - metabolism, rap1 GTP-Binding Proteins - metabolism, ras Proteins - metabolism, Receptors, Somatostatin - deficiency, Receptors, Somatostatin - genetics, Receptors, Somatostatin - metabolism, Somatostatin - analogs & derivatives, Somatostatin - pharmacology, Tumor Suppressor Proteins - metabolism