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The Ras/Raf/MEK/ERK pathway is activated by many growth factors and cytokines, which are important in driving proliferation and preventing apoptosis [1–5]. An overview of the effects of Ras/Raf/MEK/ERK and PI3K/Akt pathways on downstream signaling pathways leading to growth and the prevention of apoptosis is presented in Fig. 7.1. After receptor ligation, Shc, a Src homology (SH)-2 (SH2)-domain containing protein, becomes associated with the c-terminus of the growth factor receptor [6–8]. Shc recruits the GTP-exchange complex Grb2/Sos resulting in the loading of membrane bound Ras with GTP [9, 10]. Ras:GTP then recruits Raf to the membrane, where it becomes activated, likely via a Src-family tyrosine (Y) kinase [11–13]. Raf is responsible for phosphorylation of the mitogen associated/extracellular regulated kinase-1 (MEK1) [14–16]. MEK1 phosphorylates extracellular regulated kinases 1 and 2 (ERKs 1 and 2) on specific threonine (T) and Y residues [14–16]. Activated ERK1 and ERK2 serine (S)/T kinases phosphorylate and activate a variety of substrates including p90Rsk1[17–23]. p90Rsk1 can activate the cAMP response element binding protein (CREB) transcription factor (20). Moreover, ERK can translocate to the nucleus and phosphorylate additional transcription factors such as Elk1, CREB, and Fos, which bind promoters of many genes, including growth factor and cytokine genes important in stimulating the growth and survival of multiple cell types [24–35]. The Raf/ MEK/ERK pathway can also modulate the activity of many proteins involved in apoptosis, including Bcl-2, Bad, Bim, Mcl-1, caspase 9, and survivin [36–45]. Raf-1 has many roles that are independent of MEK and ERK, and many of these non-MEK/ ERK functions are involved in the prevention of apoptosis [4]. Recently Raf-1 was shown to interact with mammalian sterile 20-like kinase (MST-2) and prevent its dimerization and activation [46]. MST-2 is a kinase, which is activated by pro-apoptotic agents Chapter 7 Targeting Survival Cascades Induced by Activation of Ras/Raf/MEK/ERK and PI3K/Akt Pathways to Sensitize Cancer Cells to Therapy |
