Receptor tyrosine kinases , signaling

Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling transient versus sustained extracellular signal-regulated kinase activation. Cell 80 179-185... 

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. 

Fiorini, M., M. Alimandi, L. Fiorentino, G. Sala, and O. Segatto. Negative regulation of receptor tyrosine kinase signals. FEES Lett. 490 132-41.2001. 

Wiley, H. S., and P. M. Burke. Regulation of receptor tyrosine kinase signaling by endocytic trajficking. Traffic. 2 12-18.2001. 

Receptor Serine/Threonine Receptor Protein Kinase = Receptor Protein Phosphotyrosine Phosphatase = Receptor Tyrosine Kinase = Signal Transducer and Activator of Transcription = Transforming Growth Factor P = Tetradecanoylphorbolacetate = Tetradecanoylphorbolacetate Response Element = Change in Permeability of PM to specific solutes = Change in Transmembrane Potential. 

Ostman, A., and Bohmer, F. D. (2001). Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol 11, 258—266. 

Figure 24.20. Receptor tyrosine kinase signaling. Activation of RTKs results in autophos-phorylation, and these phosphorylated tyrosines serve as docking sites for proteins (PI3K, GRB2, GAPpl20, SRC) containing SH2 domains. Once docked, these proteins become active, thus resulting in the activation of downstream signaling proteins.

The second example of cell-signaling process that involves protein phosphorylation is receptor tyrosine kinase signaling (Fig. 10) (42). Receptor tyrosine kinases are transmembrane proteins with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain. Ligand binding to the extracellular domain triggers receptor dimerization and/or activation, so that the intracellular catalytic domains from two receptor protein molecules can phosphorylate each other at the... 

Figure 10 Receptor tyrosine kinase signaling process and the activation of MAP Kinase. (1) Binding of hormone to the receptor causes activation of the kinase activity of the receptor, which leads to phosphorylation of Tyr residues (2) pTyr residues recruit GRB2, which in turn recruit Sos (3) Sos promotes exchange of GTP for GDP in Ras, which leads to the active Ras-GTP complex. Then, Sos dissociates from the active Ras (4) active Ras binds to and activate the kinase Raf (4a) and hormone can dissociate from the receptor (4b) (5) activated Raf phosphoryates and activates MEK (6) activated MEK phosphorylates and activates of MAP kinase (7) activated MAP kinase can phosphorylate transcription factors (TF) and (8) phosphorylated translation factors then bind to DNA and lead to changes in gene transcription and ultimately cell division/differentiation.

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. 

Waters, C., Pyne, S., et al. (2004). The role of G-protein coupled receptors and associated proteins in receptor tyrosine kinase signal transduction. Semin Cell Dev Biol 15(3) 309-23. 

Zwick, E., Bange, J., et al. (2001). Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer 8(3) 161-73. 

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 ... 

Ahmad N, Gab H, Javed S, Agarwal R. Skin cancer chemopreventive effects of a flavonoid antioxidant silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell cycle progression. Biochem Biophys Res Commiin 1998 247 294-301. 

O Reilly, K.E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500-1508 (2006). 

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