Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast adenocarcinoma cells.
Somatostatin (SST) analogs exert direct antiproliferative actions in pancreatic, pituitary, and mammary tumor cells in vitro. SST receptor (SSTR)-mediated induction of membrane-associated protein tyrosine phosphatase (PTP) activity has been implicated in its anti-proliferative signaling by virtue of its ability to dephosphorylate and inactivate growth factor receptor kinases. Recently, a PTP-containing Src homology 2 domain, identified as PTP1C/SHPTP1/SHP/HCP, was found to be associated with SSTR in rat pancreatic acinar cell membranes. In the present study we investigated the antiproliferative action of the octapeptide SST analog SMS 201-995 (OCT) and its effect on PTP activity in MCF-7 human breast adenocarcinoma cells. We report here that OCT does not directly stimulate membrane-associated PTP activity, but induces translocation of intracellular PTP to the membrane in MCF-7 cells preincubated with the peptide in a time- and concentration-dependent manner. We demonstrate that this is due at least in part to OCT-induced recruitment of cytosolic PTP1C. OCT-induced recruitment of PTP1C to the cell surface as well as its ability to inhibit the growth of MCF-7 cells was G protein dependent and inhibited by orthovanadate. These findings suggest that translocation of cytosolic PTP1C by SST analogs to the cell surface is an early event in its antiproliferative signaling in tumor cells.
Srikant
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Fraser Laboratories, Royal Victoria Hospital, Montreal, Quebec, Canada. Srikant@rvhmed.lan.mcgill.ca
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D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D015282:Octreotide / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D047908:Intracellular Signaling Peptides and Proteins; D010566:Virulence Factors, Bordetella; D014638:Vanadates; D010744:Phosphoric Monoester Hydrolases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516727:Ptpn11 protein, rat; C509250:Ptpn6 protein, rat; D019204:GTP-Binding Proteins; D015282:Octreotide