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

Eur J Biochem. 2003 Apr;270(8):1828-37. doi: 10.1046/j.1432-1033.2003.03546.x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Squamous Cell
  • DNA, Neoplasm / biosynthesis
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / drug effects
  • ErbB Receptors / metabolism*
  • Humans
  • Hydrazines / pharmacology
  • Kinetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Nitric Oxide / pharmacology*
  • Nitric Oxide Donors / pharmacology
  • Nitrogen Oxides
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Thymidine / metabolism
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases


  • DNA, Neoplasm
  • Hydrazines
  • Nitric Oxide Donors
  • Nitrogen Oxides
  • Phosphotyrosine
  • Nitric Oxide
  • Epidermal Growth Factor
  • 1,1-diethyl-2-hydroxy-2-nitrosohydrazine
  • ErbB Receptors
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Thymidine