Abstract
SHP-1 (also known as PTP1C, SHPTP-1, SHP, and HCP) is an SH2 domain-containing protein-tyrosine phosphatase. We have stably overexpressed the native form and a catalytically inactive cysteine to serine mutant of the enzyme, SHP-1-(Cys --> Ser), in human cervical carcinoma HeLa cells. Following stimulation of the cells with epidermal growth factor (EGF) and interferon-gamma (INF-gamma), signal transducers and activators of transcription (STAT) activity was analyzed by using two 32P-labeled DNA probes, namely hSIE which is derived from a high affinity mutant form of the serum-inducible element in the c-fos promotor and GAS which resembles the INF-gamma activation site. EGF induced hSIE binding activity only, and the activity was suppressed by approximately 70% when the inactive mutant form of SHP-1 was expressed but was essentially unaffected by expression of the native enzyme. INF-gamma treatment resulted in appearance of both hSIE and GAS binding activities. While expression of the inactive mutant reduced the activities by 30-50%, the native enzyme caused a 20-30% increase. Consistent with effects on STAT activation, altered SHP-1 expression also affected EGF-induced activation of the mitogen-activated protein kinase pathway; expression of SHP-1-(Cys --> Ser) inhibited activity of MEK by approximately 25%, whereas expression of SHP-1 resulted in a approximately 25% increase. Further studies revealed that overexpression of SHP-1 caused decreased tyrosine phosphorylation of the EGF receptor and that EGF induced phosphorylation and recruitment of SHP-1. Together, the data suggest that SHP-1 is positively involved in EGF- and INF-gamma-induced STAT activation in non-hematopoietic HeLa cells and that, in the EGF signaling system, SHP-1 functions at least partly by modulating tyrosine phosphorylation of EGF receptor.
Highlights
SHP-1 is an SH2 domain-containing protein-tyrosine phosphatase
We have demonstrated that, in nonhematopoietic HeLa cells, expression of a catalytically inactive mutant of SHP-1 resulted in a significant decrease in epidermal growth factor (EGF)- and INF-␥-induced signal transducers and activators of transcription (STAT) activity, whereas overexpression of the native form of enzyme had no effect on the former but had a moderate positive effect on the latter
These results are consistent with the recent reports on the positive role of SHP-1 in activation of the MAP kinase pathway in human embryonic kidney 293 cells induced by serum and EGF and in macrophages induced by CSF-1 [24, 25]
Summary
23376 –23381, 1997 Printed in U.S.A. Positive Effects of SH2 Domain-containing Tyrosine Phosphatase SHP-1 on Epidermal Growth Factor- and Interferon-␥-stimulated Activation of STAT Transcription Factors in HeLa Cells*. The data suggest that SHP-1 is positively involved in EGF- and INF␥-induced STAT activation in non-hematopoietic HeLa cells and that, in the EGF signaling system, SHP-1 functions at least partly by modulating tyrosine phosphorylation of EGF receptor. Recent studies demonstrated that SHP-1 suppresses interferon-␣/- and erythropoietin-stimulated activation of STATs by dephosphorylating JAK1 and JAK2, respectively [14, 15] This is consistent with its negative role in other signaling mediated by interleukin-3 receptor [16], c-kit [17, 18], colony-stimulating factor-1 receptor [19], B-cell antigen receptor [20], and T-cell antigen receptor [21]. We demonstrate that, in nonhematopoietic HeLa cells, SHP-1 is positively involved in EGFand INF-␥-induced STAT activation
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