Mitogen-activated protein kinase cell-surface receptors

A recently identified thyroid hormone cell surface receptor on the extracellular domain of integrin alphaVbeta (3) leads to the activation of the mitogen-activated protein kinase (MAPK) signal transduction cascade in human cell lines, Examples of MAPK-dependent thyroid hormone actions are plasma membrane ion pump stimulation and specific nuclear events, These events include serine phosphorylation of the nuclear thyroid hormone receptor, leading to co-activator protein recruitment and complex tissue responses, such as thyroid hormone-induced angiogenesis, The existence of this cell surface receptor means that the activity of the administered hormone could be limited through structural modification of the molecule to reproduce only those hormone actions initiated at the cell surface (8,9). 

Further evidence for the importance of imine formation for T cell function was derived from the discovery that tucaresol and other small molecules with an aromatic aldehyde moiety capable of forming Schiff bases, produces a signal to CD4+ T helper (Th) cells [62]. Tucaresol reacts in vitro with free CD4+ T cell surface amines from receptors like CD2 within seconds to cause a co-stimulatory signal to produce a Thl response with the release of interferon y (IFN-y) and a 5- to 10-fold increase of interleukin 2 (IL-2). Such a Thl response is believed to be important for intracellular pathogens such as viruses, mycobacteria, protozoa and tumors. Studies in vivo show that low concentrations of tucaresol enhance not only CD4+ Th cells in response to antigens but also CD 8+ CTL and that this response has a beneficial effect in antiviral and antitumor therapy in animal models. Mechanistically, formation of Schiff bases with tucaresol has been shown to greatly affect intracellular potassium and sodium ion concentrations by the co-stimulation of mitogen-activated protein kinase (MAP kinase) and thus activation of ion channels in T cells [62,102]. Some of these mechanistic features are depicted in Fig. 19. 

In osteoblasts, keratinocytes, and colonocytes, andpossibly other cells, calcitriol acts via cell surface receptors linked to phospholipase C, resulting in release of diacylglycerol and inositol trisphosphate (Section 14.4.1), followed by opening of intracellular calcium channels and activation of protein kinase C and mitogen-activated protein (MAP) kinases. The effect of this is inhibition of cell proliferation and induction of differentiation. A variety of analogs of calcitriol that do not bind to the nuclear receptor do bind to, and activate, the cell surface receptor, including l,25-dihydroxy-7-dehydrocholesterol and 1,25-dihydroxylumisterol. The rapid nongenomic responses to vitamin D can be demonstrated in knockout mice that lack the vitamin D nuclear receptor (Farach-Carson and Ridall, 1998 Nemere and Farach-Carson, 1998). 

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