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MAP Kinase Pathways

In mammalian cells all receptor tyrosine kinases (RTKs), as well as most cytokine receptors, appear to utilize a highly conserved signal-transduction pathway in which the signal induced by ligand binding is carried via GRB2 and Sos to Ras, leading to its activation (see Figure 14-16). Activated Ras pro motes formation at the membrane of signaling complexes containing three sequentially acting protein kinases that are associated with a scaffold protein. This kinase cascade culminates in activation of MAP kinase, a serine/threonine kinase also known as ERK. After translocating into the nucleus, MAP kinase can phosphorylate many different proteins, including transcription factors that regulate expression of important cell-cycle and differentiation-specific proteins. Activation of MAP kinase in two different cells can lead to similar or different cellular responses, as can its activation in the same cell following stimulation by different hormones.

In this section, we first examine the components of the kinase cascade downstream from Ras in RTK-Ras signaling pathways in mammalian cells. Then we discuss the linkage of other signaling pathways to similar kinase cascades, and we examine recent studies indicating that both yeasts and cells of higher eukaryotes contain multiple MAP kinase pathways.

Signals Pass from Activated Ras to a Cascade of Protein Kinases

A remarkable convergence of biochemical and genetic studies in yeast, C. elegans, Drosophila, and mammals has revealed a highly conserved cascade of protein kinases that operates in sequential fashion downstream from activated Ras (Figure 14-21). Active Ras-GTP binds to the N-terminal regulatory domain of Raf, a serine/threonine kinase, thereby activating it (step 2 ). Hydrolysis of Ras-GTP to Ras-GDP releases active Raf (step 3), which phosphorylates and thereby activates MEK (step 4). Active MEK then phosphorylates and activates MAP kinase, another serine/threonine kinase (step 5). (A dual-specificity protein kinase, MEK phosphorylates its target proteins on both tyrosine and serine or threonine residues.) MAP ki-nase phosphorylates many different proteins, including nuclear transcription factors, that mediate cellular responses (step 6).

Several types of experiments have demonstrated that Raf, MEK, and MAP kinase lie downstream from Ras and have revealed the sequential order of these proteins in the pathway. For example, mutant Raf proteins missing the N-terminal regulatory domain are constitutively active and induce quiescent cultured cells to proliferate in the absence of stimulation by growth factors. These mutant Raf proteins were initially identified in tumor cells; like the constitutively active RasD protein, such mutant Raf proteins are said to be encoded by oncogenes (Chapter 23). Conversely, cultured mammalian cells that express a mutant, nonfunctional Raf protein cannot be stimulated to proliferate uncontrollably by a constitutively active RasD protein. This finding established

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Ras activated by exchange of GDP for GTP

Active Ras recruits, binds, and activates Raf

GTP hydrolysis leads to dissociation of Ras from Raf

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