Abnormalities of structure, function, expression, and signal transduction of ERK in relation to carcinogenesis

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We found a point mutation at the codon 322 from glutamic acid (E) to lysine (K) within the CD domain of ERK2 of a cell line (HSC6) established from human oral squamous cell carcinoma. In this study we aimed to elucidate (1)biochemical, biophysical, and biological changes of ERK2 mutant by comparing with the normal couterpart and (2) incidence of such mutations in oral cancer. By these studies, we anticipated to get an answer how E322K mutation plays a role in the genesis of cancer. The results obtained are (1) E322K protein lost activity to bind MAPK phosphatase, resulting in constitutive activation of mutant protein, (2) cells exogenously expressing E322K gained growth advantage in soft agar, (3) E322K showed slightly less neurite-like forming activity in PC12 cells, (4) transgenic D, rosophila carrying E322K showed weak abnormality in development of compound eye and (5) no significant mutation was found except for 3 cases of polymorphic base changes in the CD domain out of 88 oral cancer samples. These results suggested that E322K mutant has weak activity toward cellular transformation and abnormal development but the incidence of mutation was low if there is.Besides, we obtained results suggesting (1) that SNT-2 binds to preferentially phosphorylated ERK and to EGF receptor, which results in down-regulation of EGF signaling by a feed back loop mechanism, (2) that aberrant expression of Naf1, another ERK2 binding protein, was observed in oral cancer cell lines and this protein may protect cells from apoptosis in G2/M-arrested cells