Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines

The ability of cancer cells to proliferate abnormally and invade surrounding tissue is among the most important features of the malignant phenotype. The mechanisms by which the mitogen activated protein kinase (MAPK) cascade regulates these phenotypes have been investigated for many years. Activated GTP bound Ras binds the upstream protein kinases Raf-1 and B-Raf. The MAPK kinases I and 2, known as MKK or MEK, are phosphorylated and activated by Raf. MEKs phosphorylate the extracellular signal regulated kinases ERK1 and ERK2. A unique member of the MAPK family is p97(MAPK) the human homolog of rat ERK3. p97(MAPK) is ubiquitously expressed but whether its cellular functions are different from ERK1 and ERK2 is unknown. p97(MAPK) is highly expressed in human cancer cell lines. In the present study, expression of p97(MAPK) was unique among the ERK family in that its expression was induced when human carcinoma cell lines are plated on type TV collagen. This increased expression correlated with slower cancer cell proliferation on collagen compared to plastic tissue culture dishes. Overexpression of p97(MAPK) was sufficient to inhibit cellular proliferation with concomitant changes in cell cycle regulatory protein expression. p97(MAPK) also inhibited cancer cell migration and invasion by decreasing Rac1 expression but not that of matrix metalloproteinase 9 which is regulated by other ERKs. These data represent the first reported function of p97(MAPK) in human cancer cells.