Inactivation of Protein-tyrosine Phosphatases as Mechanism of UV-induced Signal Transduction

Abstract

UV irradiation of cells causes ligand-independent acChanges in gene expression are induced by extracellular stimuli most of which are perceived by cell surface receptors. One major class of surface receptors, receptor tyrosine kinases, are primed to react to specific growth factors. Upon ligand binding, the receptor subunits mutually phosphorylate each other. The phosphorylated tyrosine peptide motifs then become docking sites for numerous proteins of the signal transduction network. Most data are compatible with the idea that the ligand triggers this activity of receptor tyrosine kinase by stabilizing the association of subunits (1, 2).In addition to physiologic stimuli, many adverse agents such as carcinogens, metal toxins, oxidants, and radiation can induce signal transduction cascades and changes in gene expression. Ultraviolet (UV) 1 radiation of various wavelength has received most attention. The response to UV appears to depend on several primary radiation target molecules (3, 4). Interestingly, part of the immediate response to UV is mediated by the ligand-independent activation of growth factor receptors (5-7). For instance, the epidermal growth factor receptor (EGFR) and the platelet-derived growth factor receptor (PDGFR) are autophosphorylated within seconds of UV irradiation of cells in culture. The autophosphorylation appears to lead to fully functional receptor signaling, best shown for the EGFR (5, 8 -10) and the insulin receptor (6). Several components of signal transduction, Grb-2, phospholipase C-␥, and Shc that contain SH2 domains or phosphotyrosine-binding domains associate with the receptors in UV-irradiated cells. In consequence, Ras and the Ras-dependent signal transduction pathway to Erk and several other signaling pathways (11) are activated. From the successful activation by UV of receptor heterodimers the conclusion has been derived that a substantial fraction of the receptor tyrosine kinases are in dimer configuration in the absence of ligand and prior to the UV stimulus (Ref. 12, and references therein).How can an unspecific agent such as UV lead to a gain of function: up-regulation of enzymatic activity of the receptors? One suggestion has been, that UV causes cross-links of associated receptor monomers. The dose of UV that would be needed to substantially cross-link proteins, is, however, at least 1 order of magnitude higher than that efficiently activating the receptors. Clustering has, however, been observed for the tumor necrosis factor receptor after UV irradiation (7). It is not clear whether the clustering represents the primary event or whether it is the result rather than the cause of activation. An alternative suggestion has been derived from comparative studies of the kinetics of receptor dephosphorylation with or without UV irradiation (9). UV strongly retards dephosphorylation of both, EGFR and PDGFR. In vitro, irradiation of a plasma membrane vesicle preparation containing phosphatase inactivated the enzymatic activity, compatible with the idea that specific receptor-...

Ultraviolet-B Activates Components of the Systemin Signaling Pathway in Lycopersicon peruvianum Suspension-cultured Cells

“…Moreover, activation of MAPK cascades by some forms of oxidative stress have been shown to depend on generation of reactive oxygen species (33,53). In animal cells, oxidative processes appear to be the mechanism by which growth factor receptors are activated in response to UV light (7)(8)(9).…”

“…The receptor tyrosine kinases are most likely not the primary targets of UV radiation. There is evidence showing that these receptors are activated as a consequence of UVinduced inhibition of tyrosine phosphatases (7)(8)(9).…”

Free Radicals in the Physiological Control of Cell Function

“…This effect is to some extent, albeit not exclusively, the consequence of the oxidative inhibition of protein tyrosine phosphatases. Massive inhibition associated with increased net phosphorylation of receptor tyrosine kinases is induced by various types of strong oxidative stress, including high doses of ROS, UV irradiation, or alkylating agents (43,44,139,217,245,251,313,555). Protein tyrosine phosphatases counteract the effect of protein tyrosine kinases and reset membrane receptors after ligand-induced autophosphorylation.…”

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