Session 6: Signal transduction in the light membrane structure
How might relocalization of receptors to a new membrane compartment enhance, terminate or otherwise alter signalling?
Judith Klumperman
Activation of receptor tyrosine kinases (RTKs) by growth factors initiates many different signalling cascades, resulting in cell growth and proliferation. To avoid uncontrolled cell division, receptor activation must be in tight balance with signal attenuation: overactivation of RTK signalling pathways as well as impaired deactivation of RTKs is strongly associated with carcinogenesis. An important mode of signal attenuation is the degradation of RTKs in lysosomes, which is also known as downregulation. Downregulation begins with the uptake of RTKs from the cell surface via clathrin-mediated endocytosis, followed by their transfer to endosomes. A prerequisite for their subsequent transport to lysosomes is that the RTKs are incorporated into small vesicles that form by inward budding of the endosomal limiting membrane. Importantly, by this sorting step, the receptors are segregated from the cytosolic signalling machinery, prohibiting further signalling.
RTK activation often results in ubiquitination of the receptor and/or an accessory protein, which is required for endocytosis and sorting to lysosomes. However, some RTKs, such as HER2, are resistant to ubiquitin-induced downregulation. Consequently, activated HER2 is poorly endocytosed, and once internalized, it is recycled to the plasma membrane while it continues signalling. Intriguingly, and in seeming contrast with the above-mentioned role of endosomes in RTK sorting, a role is emerging for endosomes as signalling platforms. It is of interest to consider our increasing knowledge of the relationships between intracellular signalling and trafficking.
Further reading
Bache, K. G., Slagsvold, T. & Stenmark, H. Defective downregulation of receptor tyrosine kinases in cancer. EMBO J. 23, 2707-2712 (2004)
Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893-905 (2002)
Miaczynska, M., Pelkmans, L. & Zerial, M. Not just a sink: endosomes in control of signal transduction. Curr. Opin. Cell Biol. 16, 400-406 (2004)
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