INVOLVEMENT OF THE PROTEIN-TYROSINE-PHOSPHATASE SHP-1 IN RAS-MEDIATEDACTIVATION OF THE MITOGEN-ACTIVATED PROTEIN-KINASE PATHWAY

Ubiquitously expressed SH2-containing tyrosine phosphatases interact p hysically with tyrosine kinase receptors or their substrates and relay positive mitogenic signals via the activation of the Ras-mitogen-acti vated protein kinase (MAPK) pathway. Conversely, the structurally rela ted phosphatase SHP-1 is predominantly expressed in hemopoietic cells and becomes tyrosine phosphorylated upon colony-stimulating factor 1 t reatment of macrophages without associating with the colony-stimulatin g factor 1 receptor tyrosine kinase. Mice lacking functional SHP-1 (me /me and me(v)/me(v)) develop systemic autoimmune disease with accumula tion of macrophages, suggesting that SHP-1 may be a negative regulator of hemopoietic cell growth, By using macrophages expressing dominant negative Ras and the me(v)/me(v) mouse mutant, we show that SHP-1 is a ctivated in the course of mitogenic signal transduction in a Ras-depen dent manner and that its activity is necessary for the Ras-dependent a ctivation of the MAPK pathway but not of the Raf-l kinase. Consistent with a role for SHP-1 as an intermediate between Ras and the MEK-MAPK pathway, Ras-independent activation of the latter kinases by bacterial lipopolysaccharide occurred normally in me(v)/me(v) cells, Our result s sharply accentuate the diversity of signal transduction in mammalian cells, in which the same signaling intermediates can be rearranged to form different pathways.