Protein tyrosine phosphatase inhibitors in Fc gamma RI-induced myeloid oxidant signaling.
Fc-receptor stimulation in myeloid cells results in increased oxygen consumption, termed the respiratory burst, which is coupled to a rapid and transient increase in tyrosine phosphorylation of cellular proteins. In a previous paper in this journal we showed that the protein tyrosine phosphatase (PTPase) inhibitors sodium orthovanadate and phenylarsine oxide (PAO) block the Fc gamma RI-induced respiratory burst in interferon-gamma-differentiated U937 cells (U937IF) while augmenting the Fc gamma RI-induced tyrosine phosphorylation of cellular proteins. Herein we examine the effects of PTPase inhibitors on specific molecules involved in Fc gamma RI signaling. We show that orthovanadate and PAO augmented the Fc gamma RI-induced tyrosine phosphorylation of the adaptor protein CBL. CBL interactions with other phosphoproteins, among them SHC and CRKL, were also augmented in response to pretreatment with the PTPase inhibitors. SHC was tyrosine phosphorylated in response to Fc gamma RI stimulation of U937IF cells and bound to the SH2 domain of GRB2 in a stimulation-dependent manner. In fusion protein pull-down experiments the interaction of SHC with the SH2 domain of GRB2 was increased in PTPase inhibitor pretreated U937IF cells in response to Fc gamma RI stimulation. Our data support the hypothesis that a tyrosine dephosphorylation event is required for effective transmission of the Fc gamma RI signal to result in activation of the myeloid respiratory burst response.
Erdreich-Epstein
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Neil Bogart Memorial Laboratory, Department of Pediatrics, Childrens Hospital Los Angeles, University of Southern California School of Medicine 90027, USA.
Liu
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Liu
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Durden
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D001152:Arsenicals / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007962:Leukocytes / Q000201:enzymology*; D019000:Phosphotyrosine / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D017452:Receptors, IgG / Q000502:physiology*; D016897:Respiratory Burst; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D014638:Vanadates / Q000494:pharmacology
D001152:Arsenicals; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; C029341:oxophenylarsine; D019000:Phosphotyrosine; D014638:Vanadates; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D017027:Protein Tyrosine Phosphatases; C067419:CBL protein, human