Receptor tyrosine kinases signaling pathways

To understand something about how this works, I need to describe a signaling pathway associated with cell growth. There are at least eight of these 1 shall describe one—the receptor tyrosine kinase signaling pathway—as an example, omitting a fair amount of detail. It is summarized in figure 24.1. 

Why is the signaling pathway that activates NF-kB considered to be relatively irreversible compared to cytokine or receptor tyrosine kinase signaling pathways Nonetheless, NF-kB signaling must be downregulated eventually. How is the NF-kB signaling pathway turned off ... 

Protein tyrosine phosphatases play a crucial role in the control of the activity of receptor tyrosine kinases, nonreceptor tyrosine kinases, and the signaling pathways that they regulate. The importance of the tyrosine phosphatases for receptor tyrosine kinase signaling is illustrated by the observation that virtually all receptor tyrosine kinases can be activated, even in the absence of ligand, by treatment of cells with tyrosine phosphatase inhibitors, demonstrating that the activity of tyrosine kinases is continuously controlled by inhibitory tyrosine phosphatase action. As outlined above, the activity of most receptor tyrosine kinases is positively controlled by Tyr-phosphorylation in the activation loop. Protein tyrosine phosphatases that remove these stimulatory phosphate residues will inhibit receptor activity and the biological responses mediated by Tyr-phosphorylation-dependent signaling pathways. 

PKA and PKC are, however, not the only kinases to regulate TRPVl. The Ca /calmodulin-dependent kinase II (CaMKII) sensitizes TRPVl by phosphorylation [57, 58], as does phophatidylinositol 3-kinase (PI3K) via its downstream target AKT [59]. This latter finding links TRPVl to the ERK (extracellular signal-regulated protein kinase) pathway. The non-receptor tyrosine kinase Src likewise potentiates capsaicin-induced currents [60]. 

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.

Receptor tyrosine kinases are critical components of signaling pathways that control cell proliferation and differentiation. Enhanced RTK activity due to activating mutations or overexpression has been implicated in human cancers. Thus, selective inhibitors of RTKs have considerable value. Although a number of compounds have been identified as effective inhibitors of RTKs,... 

Store it while it s here. Insulin binds to a specific receptor on the cell surface and exerts its metabolic effect by a signaling pathway that involves a receptor tyrosine kinase phosphorylation cascade. Note that insulin stimulates storage processes and at the same time inhibits degradative pathways. 

CREB is also phosphorylated on serine 133 by stimulation of growth factor signaling cascades [63]. This occurs via a complex pathway involving MAPK cascades (Fig. 23-9). Thus, as outlined earlier, nerve growth factor and related neurotrophins that act on receptor tyrosine kinases lead to the successive activation of Ras, Raf, MEK and ERK. Activated ERK then phosphorylates and activates a serine-threonine kinase, RSK, particular subtypes of which directly activate CREB via the phosphorylation of serine 133. 

The coupling of superantigen—major histocompatibility complex class II to T-cell receptor swifdy results in cell-signaling cascades. ° These staphylococcal toxins can increase levels of phosphatidyl inositol from quiescent T cells, such as other mitogens, as well as elicit intracellular Ca movement that activates the protein kinase C (PKC) pathway important for interleukin-2 (IL-2) expression. " IL-2 is intimately linked to T-cell proliferation. In addition to the PKC pathway, the protein tyrosine kinase (PTK) pathway is also activated by superantigens, leading to elevated expression of various proinflammatory cytokines. Staphylococcal superantigens also potently activate transcriptional factors NF-/IB (nuclear factor kappa B) and AP-1 (activator protein-1), which subsequently elicit the synthesis of proinflammatory cytokines. " " ... 

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