Tyrosine phosphorylation of proteins is required for signal transduction in cells and for growth regulation. A mitogen-induced gene ( PAC-1 ) has been cloned from human T cells and encodes a 32-kilodalton protein that contains a sequence that defines the enzymatic site of known protein phosphotyrosine phosphatases (PTPases). Other than this sequence, PAC-1 is different from several other known related PTPases exemplified by PTP-1b. PAC-1 is similar to a phosphatase induced by mitogens or heat shock in fibroblasts, a yeast gene, and a vaccinia virus-encoded serine-tyrosine phosphatase (VH1). PAC-1 was predominantly expressed in hematopoietic tissues and localized to the nucleus in transfected COS-7 cells and in mitogen-stimulated T cells.

Microphthalmic (mi/mi) mice are unpigmented, osteopetrotic, mast cell deficient, and exhibit diminished gastric acid secretion and natural killer cell activity. In order to assess the effect of this mutation on macrophage function, we studied superoxide (O2-) and nitric oxide (NO) production, superoxide dismutase (SOD) activity, phagocytic capacity, and tumor cell killing by peritoneal macrophages from mi/mi mice and normal (+/+) litter mates. Macrophages from mi/mi mice, upon activation with phorbol myristate acetate (PMA), generated significantly higher amounts of O2- than did macrophages from their +/+ litter mates. The phagocyte respiratory burst as assessed by nitroblue tetrazolium (NBT) reduction assay also displayed a 2-fold enhancement in mi/mi macrophages. The assay of SOD activity revealed significantly lower levels in mi/mi macrophages than in the wild type. Furthermore, in comparison with controls, macrophages from mi/mi mice demonstrated significantly higher levels of NO production and increased capacity to lyse tumor cells upon activation with lipopolysaccharide (LPS) or gamma-interferon (IFN-gamma). The mi mutation, therefore, is associated with reduced macrophage SOD activity, increased O2- and NO production, and enhanced capacity for tumor cell killing. The molecular mechanisms for these changes have not been identified.