Nitric oxide‐induced epidermal growth factor‐dependent phosphorylations in A431 tumour cells

Publisher Website
Google Scholar
Abstract
Nitric oxide (NO•) strongly inhibits the proliferation of human A431 tumour cells. It also inhibits tyrosine phosphorylation of a 170‐kDa band corresponding to the epidermal growth factor receptor (EGFR) and induces the phosphorylation at tyrosine residue(s) of a 58‐kDa protein which we have denoted NOIPP‐58 (nitric oxide‐induced 58‐kDa phosphoprotein). The NO•‐induced phosphorylation of NOIPP‐58 is strictly dependent on the presence of EGF. Phosphorylation of NOIPP‐58 and inhibition of the phosphorylation of the band corresponding to EGFR are both cGMP‐independent processes. We also demonstrate that the p38 mitogen‐activated protein kinase (p38MAPK) pathway is activated by NO• in the absence and presence of EGF, whereas the activity of the extracellular signal‐regulated protein kinase 1/2 (ERK1/2) and the c‐Jun N‐terminal kinase 1/2 (JNK1/2) pathways are not significantly affected or are slightly decreased, respectively, on addition of this agent. Moreover, we show that the p38MAPK inhibitor, SB202190, induces rapid vanadate/peroxovanadate‐sensitive dephosphorylation of prephosphorylated EGFR and NOIPP‐58. We propose that the dephosphorylation of both NOIPP‐58 and EGFR are mediated by a p38MAPK‐controlled phosphotyrosine‐protein phosphatase (PYPP). Activation of the p38MAPK pathway during nitrosative stress probably prevents the operation of this PYPP, allowing NOIPP‐58, and in part EGFR, to remain phosphorylated and therefore capable of generating signalling events.