Cellular motility, a prerequisite for
metastasis of
tumor cells, is affected by a 55-kDa
tumor-cell-secreted
cytokine which influences the migration of the producing cells and is called
autocrine motility factor (AMF). Previous studies indicated that AMF stimulates motility by binding to its receptor, a
cell-surface glycoprotein of 78 kDa (gp78), inducing its phosphorylation, activating a
pertussis toxin (PT)-sensitive
G-protein, and stimulating
inositol metabolism. However, the intracellular signaling mechanisms which transduce and regulate the AMF motility response remain largely unknown. 12-(S)-HETE, a
lipoxygenase metabolite of
arachidonic acid which affects the cytoskeletal architecture of murine
melanoma cells, also stimulates cell motility independently of PT-sensitive
G-proteins and up-regulates gp78 surface expression. 12-(S)-HETE induces the phosphorylation of gp78 in a manner analogous to AMF and the motility response of these murine
melanoma cells to both AMF and 12-(S)-HETE is inhibited by
protein kinase C inhibitors. Furthermore, perturbation of the
AMF receptor stimulated endogenous biosynthesis of 12(S)
HETE. These results suggest the existence of an "autocrine motility cycle" which influences
melanoma cell motility by gp78 activation, and production of second messengers which affect the cytoskeletal architecture and expression of the
AMF receptor itself.