Signal Transduction
depend upon phosphorylation mediated by MAP kinase, affecting contact with coactivator molecules. Ligand-independent activation occurs in some cancerous conditions. In cancer of the prostate, for example, ER and AR may be activated in the absence of an androgenic stimulus in cells exposed to the cytokine IL-6. Again, MAP kinase activation is implicated.
Non-transcriptional actions of nuclear receptors and their ligands
To add yet another layer of complexity, some responses activated by nuclear receptor ligands take place so rapidly (in seconds to minutes) that they cannot be accounted for by a transcriptional mechanism. Furthermore, membraneimpermeant ligands (e.g. steroid hormones fused to a polypeptide), are also effective, indicating the presence of some kind of receptor at the plasma membrane. Commonly, the consequence of steroid hormone binding to plasma membrane-associated receptors is to activate cytosolic signalling pathways through the production of second messengers. Such signalling effects are described as ‘non-genomic’ or ‘non-transcriptional’.
The presence of oestrogen binding sites at the plasma membrane was first reported in 197739 and there are now many examples of steroid actions initiated at the cell surface.40 The intracellular pathways that are activated vary, and
our understanding of the mechanisms involved is limited. Hormone binding to plasma membrane steroid receptors has been shown to activate PLC , adenylyl cyclase,41 PI 3-kinase, and MAP kinases in a variety of systems.42, 43 For example in osteoblasts, 1,25–dihydroxycholecalciferol (calcitriol), estradiol, or progesterone causes an elevation of intracellular Ca2 within 5 s by activating PLC in a G-protein-dependent fashion.44, 45 In a cancer cell line, androgens can activate Src within 1 min leading to MAP kinase activation. In connection with the vascular protective affects of oestrogens, ER has been shown to couple to the regulatory subunit of PI 3-kinase. Estradiol can activate this lipid kinase to produce 3-phosphoinositides which in turn recruit PKB, leading to the activation of nitric oxide synthase (eNOS) in vascular endothelial cells.46, 47
Whether the same receptors mediate both the rapid and the nuclear responses is not always clear. Prompt effects of steroids may not involve interaction with nuclear receptors at all, the ligands binding to membranelocated effector proteins or receptors. For example, progesterone modulates the effect of the peptide hormone oxytocin, by interacting directly with
the oxytocin receptor (see page 27). Also, the modulation of ion channels in the nervous system by oestrogens, without involvement of ERs, is well
documented.48 In general, it seems likely that the non-transcriptional actions of steroid hormones produce effects that facilitate or might even be a prerequisite for transcriptional signalling by the same ligand.
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