Sequential protein kinase reactions involve the phosphorylation and activation of multiple kinases in a pathway. The growth factor receptor tyrosine kinase regulation of the mitogen-activated protein kinase (MAPK) pathway was defined in 1993. The MAPK pathway involves sequential protein kinase reactions. Notable advances were made in defining tyrosine kinase receptor regulation of Ras, and these discoveries were combined with the identification of Raf-1, a serine-threonine protein kinase in the MAPK pathway, as an effector for Ras GTP.