Molecular mechanisms of cross-talk between growth factors and nuclear receptor signaling

Abstract

Signaling pathways can be linear, but more complex patterns are common. Growth factors and many other extracellular signals cannot directly enter cells and transduce their information via membrane-bound receptors. In contrast, steroid receptors are members of the nuclear receptor superfamily and await their cognate hormones inside the cells. These two types of signaling pathways are extensively intertwined and cross-talk at many different levels. A wide range of extra-and intracellular signals, including a variety of growth factors, can activate the transcriptional activity of steroid receptors in the absence of their cognate hormones. Conversely, steroid receptors lead a double life. By coupling to signaling molecules that mediate signal transduction of extracellular factors, they can elicit very rapid nongenomic responses. The signaling pathways of steroid-independent activation of steroid receptors, on the one hand, and of nongenomic signaling by steroid receptors, on the other, display a remarkable reciprocal relationship suggesting that these two modes of signaling cross-talk may be two faces of the same coin. DEFINITION AND OVERVIEWExtracellular signals modify intracellular processes through cognate receptors that elicit a cascade of events. However, a linear view of signal transduction falls short of describing all effects. Instead, branching, feedback, integration, and networking are characteristics of most if not all signal transduction pathways. Signaling cross-talk refers to a situation where one signal affects the output of another, seemingly distinct, signal transduction pathway.There is signaling cross-talk at all levels of signaling, from affecting availability of the signal to modifying the regulation of expression of target genes. For example, at the level of an organism, steroid hormone concentrations are influenced by signals that affect the levels of their serum binding proteins. Signals can stimulate the biosynthesis of other signals and their receptors. In breast cancer cells, estrogen induces the expression of the progesterone receptor (PR) [1], the EGF receptor [2], and several members of the EGF ligand family [3,4]. With respect to a target cell, signaling cross-talk may take place in the extracellular space or within the cell, inside or outside the nucleus.In this review, I will focus on the molecular mechanisms by which a variety of extra-and intracellular signals can modulate the activities of steroid receptors, in particular the receptors for the sex steroids, that is, the estrogen receptors (ERs) α and β, PR, and the androgen receptor (AR). These are all members of the nuclear receptor superfamily. Moreover, I will discuss how the very same nuclear receptors appear to elicit very rapid nongenomic effects by feeding into other signaling pathways. There is mounting evidence that these two nuclear receptor activities may be two faces of the same coin

Minireview: Tipping the Balance: Ligand-Independent Activation of Steroid Receptors

“…Even though the cross talk between the EGF signal transduction pathway and ER signaling had been well documented (85,86), only a little progress had been made toward understanding the molecular mechanisms that make the ERs effectors of the EGF pathway. In this regard, our identification of AF-1 of ER␣ as the region targeted by EGF had begun to shed light on the mechanism and emphasized the differences with estrogens, which bind the C-terminal HBD and turn on both AF-1 and AF-2 (47).…”

Ten Years of Mixing Cocktails: A Review of Combination Effects of Endocrine-Disrupting Chemicals

“…However, the molecular mode of action is different in both cases. Furthermore, the phenomenon of ligand-independent activation of steroid receptors (e.g., by phosphorylations via mitogen-activated phosphokinase cascades and activation of receptor tyrosine kinases) has become well-established ( Picard 2003 ), and steroid hormones themselves are able to induce these signaling events. If a similarity criterion for estrogens is defined in a strict molecular way, for example, solely in terms of binding to the E 2 -binding pocket with subsequent activation of the helix 12 “mousetrap” mechanism, then a wealth of additional mechanisms of ER activation would be left disregarded, although these processes may well contribute to joint effects in living organisms.…”

Endocrine disruptors from the environment affecting breast cancer (Review)

“…Interestingly, this cross-communication can occur at different places of the target cell. For instance, beyond the classical ER genomic pathway, steroids can also elicit a rapid non-genomic cascade via secondary signaling pathways due to its subtype or receptor localized in the membrane, therefore activating the mitogen-activated protein kinase MAPK cascade (69). The mitogen-activated protein kinase is in turn related to different mitogens and oncogenes enlarging the spectrum of interactions to eventually modulate DNA sequences related to proliferation or even anti-apoptotic processes (69).…”