The MAP Kinase Pathway Leads to the Expression of Cyclins and Other Stimulators of the Cell Cycle
GTP-bound Ras causes the sequential activation of a series of protein kinases, called Raf, Mek, and Erk. That is, Raf phosphorylates and activates Mek, which in turn phosphorylates and activates Erk, as shown in Figure 2-5.
This trio of kinases is called the mitogen-activated protein kinase, or MAP kinase, pathway (a mitogen is a stimulator of mitosis, e.g., a growth factor). If any of these three protein kinases should experience a gain-of-function mutation irreversibly activating the protein kinase, a stimulatory signal is sent down the remainder of the pathway. Thus, as with ras, these three kinase genes act as oncogenes. In addition, Raf, Mek, and Erk are a specific example of yet another conserved but diverse general “module” of information transduction. That is, there are MAP kinase trios other than Raf, Mek, and Erk. Although it is not worthwhile to give names to all the various specific pathways, it should be noted that these trios have a systematic set of names for their elements. Raf is a MAP kinase, kinase, kinase (a MAPKKK). Mek is a MAP kinase, kinase (MAPKK), and Erk protein is the MAP kinase (MAPK) itself. This jargon is awkward, but it is widely used and logical, as Figure 2-5 suggests.When activated, Erk activates one or more transcription factors that control the transcription and translation of a key regulator of the cyclin-CDK engine. One of these transcription factors, Myc (“mick”), is encoded by another important oncogene/proto-oncogene. As with ras, the myc gene is mutated in a high frequency of human tumors, giving rise to an oncogenic form able to activate the cell cycle. As shown in Figure 2-5, Myc protein is involved in the transcription of a
variety of cyclins and of the CDK2 catalytic subunit and plays a significant role in allowing the cell to pass from Gl to S phase. Myc is also involved in many other transcription events related to cell growth, differentiation, and cancer.
This completes the growth stimulatory pathway beginning with a growth factor binding to its RTK receptor that, through Ras, a MAP kinase cascade, and a transcription factor, eventually leads to a direct “throttling up” of a cyclin-CDK engine. This same pathway is used similarly to transduce the information about the other major stimulator of cell division, cell attachment.