RAS and the MAP Kinase Signaling Pathway

Mulations in the genes coding for any of the signaling proteins could conceivably result in the constitutive (continual) operation of the signaling pathway and the consequent maintenance of cell growth. 

Very Simple Version of the MAP Kinase Signaling Pathway 

JUN forms a dimer with itself to form JUN-JUN, a homodimer. JUN also forms a dimer with another protein, called FOS, to generate the heterodimer JUN-FOS- n the forms JUN-JUN and JUN-FOS, these proteins function as transcription factors- To turn to the detail of phosphorylation, the activity of JUN depends on its phosphorylation at Scr 63 and Ser 73 (Kallunki ft al., 1996). 

The cascade of phosphorylation, and consequent enzyme activation, is driven by RAS in its active form. Eventually, however, the GTP is hydrolyzed to GDP plus Pi, with the result that RAS reverts to its inactive form. GAP provokes the hydrolysis of GTP In detail, GAP binds to RAS, and this event provokes RAS to catalyze the hydrolysis of GTP (Sprang, 1997). Hydrolysis of GTP is followed by the dissociation of MAPRRK, the consequent inactivation of MAFKKK,and the eventual deactivation of all dow-nstream proteins. 

Does Anyfhifig Bad Happen When RAS Is Prevejifed from Hydrolyzing GTP  

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DNA Polymerase Can Make a Mistalte DMA Methylase Can Make a Mistake RAS and the MAP Kinase Signaling Pathway %ry Simple Version of the MAP Kinase Signaling Pathway Simple Version of the MAP Kinase Signaling Pathway... 

Figure 3. MAP kinase regulatory pathway. The MAP kinase signaling pathway begins with activation of the receptor tyrosine kinase (RTK) by exogenous signals, such as growth factors and insulin. The signal is then transmitted into the cell via activation of the Raf serine/threonine kinase either directly by the RTK or through the GTP-binding protein, Ras. The signal is then transmitted to the nucleus and to other cytoplasmic proteins via MAPKK and MAPK.

The importance of FAK is underlined by the finding that cells expressing a constitutively active form survive in suspension even though they are homeless. Here, the protein kinase is active regardless of the failure to make contact with an extracellular matrix. Rescue from apoptosis also occurs when cells express constitutively activated oncogenic forms of Ras or Src and thus activate Plj-kinase and the MAP kinase pathway. Unlike FAK, these not only prevent apoptosis but also promote proliferative signals that result in tumor formation. 

Wasylyk, B., Hagman, J. and Gutierrez-Hartmann, A. Ets transcription factors nuclear effectors of the Ras-MAP-kinase signaling pathway (1998) Trends Biochem Sd 23, 213-216... 

After activation of the TCR, there is induction of Src family tyrosine kinase (p56lek), which phosphorylates phospholipase Oyl. This is followed by the hydrolysis of phosphatidylinositol 4,5-bisphosphate, resulting in the production of diacyl-glycerol (DAG) and inositol trisphosphate (IP3). Protein kinase C is activated by DAG, which phosphorylates Ras. Ras is a GTPase and its phosphorylation induces Raf and initiation of MAP kinase signaling pathway. IP3 is involved in calcium-dependent activation of IL-2 gene expression via nuclear factor of activated T cells (NFAT). 

Fig. 3.3 The ERK/MAP kinase signaling pathway cytokines and growth factors activate tyrosine kinase to which the adaptor protein Grb2 binds. This localizes SOS to plasma membrane. RAS is then activated by SOS. Activated RAS then binds to RAF, which forms a transient membraneanchoring signal. Active RAF kinase phosphorylates MEK. The activated MEK phosphorylates ERK1/ERK2, which also migrates to the nucleus to phosphorylate ELK-1, Etsl/2 and CREB, resulting in the activation and expression of respective genes (see Color Insert)...

Most components of the RTK-Ras-MAP kinase signaling pathway are used repeatedly in the course of development and are evolutionarily conserved in a broad spectrum of animals. 

Genetic and biochemical investigations point to a function as a central effector of signal transduction via Ras proteins for the Raf kinase. Raf kinase is immediately downstream from Ras protein in the signal chain. The activated GTP form of Ras protein interacts in a specific manner with Raf kinase and thus mediates membrane localization of Raf kinase. Consequently, the protein kinase activity of Raf kinase is stimulated and the signal is transmitted further via the protein kinase cascade of the MAP kinase pathway. 

Fig. 9.11. Model of regulation and activation of Raf kinase. The active Ras.GTP complex binds and activates Raf kinase, which passes the signal on to the MAP kinase pathway. Various proteins including the 14-3-3 proteins and the molecular chaperons hsp 90 and p50 are thought to be involved in the regulation of the Raf kinase signahng function. In addition, Raf kinase is regulated by phosphorylation. Tyr phosphorylation (possibly via Src kinase) and Ser phosphorylation via protein kinase C have a stimulatory effect. In contrast, Ser phosphorylation via protein kinase A has an inhibitory effect. RTK receptor tyrosine kinase.

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