Tyrosine kinase growth factor receptors activate MAP kinase by a complex 
mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. 
The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase 
cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases 
have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate 
Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP 
kinase. Subsequently, the activated MAP kinase translocates into the nucleus 
where many of the physiological targets of the MAP kinase signal transduction 
pathway are located. These substrates include transcription factors that are 
regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and 
C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of 
signal transduction by growth factor receptors from the cell surface to the 
nucleus that results in the regulation of gene expression. Three MAP kinase 
homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP 
kinases that are similar to the rat Erk kinases have also been identified by 
molecular cloning. The human Erk1 protein kinase has been shown to be widely 
expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is 
a 41-kDa protein that is expressed ubiquitously. In contrast, a human 
Erk3-related protein kinase has been found to be expressed at a high level only 
in heart muscle and brain. The loci of these MAP kinase genes are widely 
distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and 
ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase 
gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together, 
these kinases are a more diverse group than the human erks that have been 
identified. Thus the erks are likely to represent only one subgroup of a larger 
human MAP kinase gene family. A candidate for this extended family of MAP 
kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and 
phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and 
Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative 
of the MAP kinase group that is activated by dual phosphorylation at Tyr and 
Thr.