title: Angiotensin II type 2 receptors mediate inhibition of mitogen-activated protein kinase cascade and functional activation of SHP-1 tyrosine phosphatase.
abstract: Angiotensin II type 2 (AT2) receptors are involved in the inhibition of cell proliferation as well as in apoptosis and neuronal differentiation, through intracellular signalling pathways that remain poorly defined. The present study examines the effect of AT2-receptor stimulation on growth-factor-induced pathways leading to the activation of mitogen-activated protein (MAP) kinases. In N1E-115 neuroblastoma cells, AT2 receptors inhibit the activity of MAP kinases induced by serum as well as by epidermal growth factor. The inhibitory effect of angiotensin II (Ang II) is rapid and transient, and affects both ERK1 and ERK2 (extracellular signal-related protein kinase) isoforms of the enzyme. AT2-mediated MAP kinase inactivation is not sensitive to pertussis toxin or okadaic acid, but involves a vanadate-sensitive protein tyrosine phosphatase (PTP). Expression of MAP kinase phosphatase-1 (MKP-1) is not significantly modified upon AT2-receptor activation, and insensitivity to actinomycin D also rules out transcriptional induction of other MKPs as a possible mechanism for AT2-mediated inactivation of MAP kinases. In addition, we report here that both in N1E-115 cells and in Chinese hamster ovary cells expressing recombinant human AT2 receptors, Ang II rapidly stimulates the catalytic activity of SHP-1, a soluble PTP that has been implicated in termination of signalling by cytokine and growth-factor receptors. These findings thus demonstrate functional negative cross-talk between heptahelical AT2 receptors and receptor tyrosine kinases, and suggest that SHP-1 tyrosine phosphatase is an early transducer of the AT2 receptor signalling pathway.
authors.affiliation: Institut Cochin de Génétique Moléculaire, CNRS UPR 0415, 22, rue Méchain, 75014 Paris, France.
authors.forename: K
authors.initials: K
authors.lastname: Bedecs
authors.forename: N
authors.initials: N
authors.lastname: Elbaz
authors.forename: M
authors.initials: M
authors.lastname: Sutren
authors.forename: M
authors.initials: M
authors.lastname: Masson
authors.forename: C
authors.initials: C
authors.lastname: Susini
authors.forename: A D
authors.initials: AD
authors.lastname: Strosberg
authors.forename: C
authors.initials: C
authors.lastname: Nahmias
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018797:Cell Cycle Proteins; D006224:Cricetinae; D003609:Dactinomycin / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology
chemical_list: D001798:Blood Proteins; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D011994:Recombinant Proteins; D000804:Angiotensin II; D003609:Dactinomycin; D019319:Okadaic Acid; D014638:Vanadates; D004815:Epidermal Growth Factor; D012313:RNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; 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