Ras Regulation And Signaling

The Natural Thyroid Diet

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Ras proteins are 21kDa GTP-binding proteins that function as molecular switches, cycling between active GTP- and inactive GDP-bound states. Cellular Ras activity is regulated by the opposing action of guanine nucleotide exchange factors (GEFs) that catalyze GDP dissociation, and GTPase activating proteins (GAPs) that stimulate intrinsic GTPase activity. Multiple RasGEFs and RasGAPs co-exist in most cells, increasing the diversity of signals that regulate Ras activity. Ras proteins are localized to the plasma membrane where they are poised to respond to signals initiated by the activation of cell surface receptors. Cellular Ras activity is maintained at very low levels. In response to signals such as those elicited by growth factors and hormones, Ras becomes activated in a transient manner. For cell surface receptors with tyrosine kinase activity, receptor dimerization induces tyrosine phosphorylation, thereby creating docking sites for signaling molecules such as Grb-2 and Shc, adaptor proteins comprised of SH2 and SH3 domains. Grb-2 is associated with the RasGEF SOS in the cytosol. Recruitment of Grb-2 to the activated receptor localizes SOS to the plasma membrane in close proximity to Ras, facilitating its activation. For G proteincoupled receptors, Ras is activated through second messengers such as diacylglycerol, calcium, and possibly cAMP (Busca et al., 2000; Pak et al., 2002), as well as through heterotrimeric G protein |3/y subunit- and src-mediated pathways.

In its active conformation, Ras binds to a variety of effectors. Effectors are defined as proteins that interact selectively with the GTP-bound form of Ras, and become activated as a consequence of this interaction. Three downstream effector pathways have been characterized in the most detail (Figure 1). They include members of the Raf, PI3K and RalGDS families (reviewed in Reuther et al., 2000; Shields et al.,

Figure 1. Ras signals through multiple downstream effectors including, but not limited to those illustrated here. In thyroid cells, Ras has been shown to signal through Raf-1, PI3K and RalGDS (shown in bold).

2000). Interaction between GTP-Ras and its first identified target, Raf-1, induces a conformational change that unmasks phosphorylation sites and anchors Raf-1 to the plasma membrane. Once this occurs, Raf-1 activity becomes Ras-independent. Active Raf binds to and phosphorylates MEK1/2 proteins, stimulating their kinase activity. MEK proteins are dual specificity serine/threonine and tyrosine protein kinases that phosphorylate and activate MAPK1/2 (also referred to as ERK1/2), protein kinases that play important roles in many cellular processes including the regulation of gene expression. In a similar fashion, binding of GTP-Ras to the p110 catalytic subunit of PI3K stimulates lipid kinase activity, increasing the production of second messenger phosphoinositide (3,4) P2 (PIP2) and phosphoinositide (3,4,5) P3 (PIP3). PIP3 promotes the activation of a kinase cascade that includes PDK-1, Akt (or PKB) and p70 ribosomal S6 protein kinase (p70s6k). These kinases phosphorylate numerous protein substrates with diverse roles in protein synthesis, cell proliferation and cell survival. PI3K also regulates survival through activation of Rac GTPases. Binding of GTP-Ras to RalGDS stimulates GEF activity towards the Ras-related proteins, Ral A and B. Downstream targets of Ral include phospholipase D, Rho, and Rac- and Cdc42-selective GAPs. There are a number of additional putative Ras effectors, including RasGAPs, MEKK, AF6, PKCC and Nore1. To date, activated Ras has been shown to signal through MAPK, PI3K and RalGDS in thyroid cells, effects that are markedly influenced by cAMP, an important regulator of thyroid cell function and proliferation (Figure 2).

Figure 2. Ras signaling pathways are altered by TSH. TSH elevates cAMP, which activates PKA and Rap1 in thyroid cells. PKA has been reported to disrupt signaling from Ras to Raf-1 by phosphorylating the N-terminus of Raf-1, which decreases the affinity ofRaf-1 for Ras. Activated Rap 1 binds to Raf-1, but does not stimulate its activity. It is not yet know whether Ras signals to B-Raf in thyroid cell (dashed line).

Figure 2. Ras signaling pathways are altered by TSH. TSH elevates cAMP, which activates PKA and Rap1 in thyroid cells. PKA has been reported to disrupt signaling from Ras to Raf-1 by phosphorylating the N-terminus of Raf-1, which decreases the affinity ofRaf-1 for Ras. Activated Rap 1 binds to Raf-1, but does not stimulate its activity. It is not yet know whether Ras signals to B-Raf in thyroid cell (dashed line).

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