Low extracellular pH induces activation of ERK 2, JNK, and p38 in A431 and Swiss 3T3 cells.

The mechanism by which mammalian cells respond to low environmental pH is unclear. A wide range of environmental stresses are known to induce activation of MAP kinases ERK 2, JNK and p38 and recent work has shown that low pH can activate the p38 homologue in yeast HOG1. In this study we show that ERK2 MAP kinase is activated in human A431 cells exposed to low pH media. Activation is sustained throughout low pH treatment, is reversible, and occurs maximally at pH 4 or 5. Stimulation is not accompanied by tyrosine phosphorylation of the EGF receptor or Raf-1 activation, indicating that acid conditions act via pathways independendent of those required for EGF mediated MAPK stimulation. The MAP kinase homologue JNK and MAPKAP kinase-2 reactivating kinase (p38) were also activated in A431 cells by low pH and so low pH induces parallel activation of multiple MAP kinase pathways. Strong activation of p42, and p44 ERKs as well as p38 and JNK was also found in mouse Swiss 3T3 cells treated at pH 5. These results indicate that MAP kinases may be important markers of the acid induced cellular stress that occurs in human disease.