Receptor transactivation cascades. Focus on “Effects of α1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells”

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Abstract
Receptor transactivation refers to the ability of a primary agonist, via binding to its receptor, to activate a receptor for another ligand. This situation can occur with G protein-coupled receptors (GPCRs), leading to activation of growth factor receptors. In the November 2006 issue of AJP-Cell Physiology , an interesting example is provided by Chen and colleagues ([4a][1]), in which binding of an agonist to a GPCR in primary cells leads to release of epidermal growth factor (EGF), which in turn activates the EGF receptor (EGFR).[1][2] In contrast to the pro-mitogenic role of EGFR transactivation that is typically reported, the authors have shown that EGFR transactivation in this situation results in negative feedback on GPCR-induced protein secretion. The study presented in this issue further elucidates the mechanism of the pathway. The resulting scenario illustrates several important points. First, growth factor receptor transactivation via GPCRs does not occur solely in tumor cells. Second, EGF itself (as opposed to other EGFR ligands) can be released via GPCR stimulation. Third, transactivation of a growth factor can have a negative effect on GPCR signaling. Thus, as we encounter more examples of receptor transactivation, it becomes apparent that there is a greater level of complexity to this phenomenon than was initially appreciated. One of the more complex and intriguing phenomena involved in signal transduction networks involves receptor “transactivation”, the ability of one receptor to activate another receptor via signaling events. These pathways can be viewed as a receptor transactivation “cascades”, by analogy to protein phosphorylation cascades. Transactivation of various growth factor receptors, including the epidermal growth factor receptor (EGFR), and the platelet-derived growth factor (PDGF) receptor, by G protein-coupled receptors (GPCRs) has been documented in multiple cellular model systems ([3][3], [4][4], [11][5], [13][6], [27][7]). GPCR-induced transactivation of Trk neurotrophin receptors has also been reported ([3][3], [11][5]). Receptor transactivation can potentially occur through several different mechanisms. One mechanism is through activation of intracellular protein tyrosine kinases, such as c-Src and PKC ([2][8], [33][9]), which can phosphorylate the growth factor receptor and thereby promote its activation. A more commonly reported mechanism involves release of membrane-tethered growth factors from the membrane by activation of matrix metalloproteinases (MMPs) ([12][10], [27][7], [28][11]). These growth factors, such as pro-heparin-bound (HB)-EGF ([20][12]), are released from their precursors and then bind to their cognate growth factor receptors ([17][13]). Since pro-mitogenic signaling by the primary GPCR can be mediated primarily by transactivation of a growth factor receptor, the downstream signaling cascade can be significantly attenuated when generation or response of the growth factor is inhibited ([6][14], [12][10]). Strategies that have been used to interrupt the transactivation pathway include EGFR kinase inhibitors ([10][15], [24][16]), anti-EGF antibodies ([8][17], [20][12]), and MMP inhibitors ([12][10], [30][18]). However, it is not yet clear whether transactivation of growth factor receptors is universally required for the mitogenic responses mediated by GPCRs. GPCR-induced transactivation of EGFRs has been studied in some detail. GPCR activation leads to cleavage of pro-EGF (e.g., pro-HB-EGF) ligands from the membrane ([2][8], [16][19], [31][20]), initiating the transactivation (see [Fig. 1][21]). Agonist-bound GPCRs activate numerous MMPs ([6][14]), including MMP-3 ([19][22]), MMPs 2 and 9 ([18][23], [28][11]), as well as members of the ADAM family of metalloproteases: ADAM10, ADAM15, and ADAM17 ([7][24], [29][25], [32][26]). The molecular mechanisms underlying GPCR-induced MMP activation are not yet clear. MMPs, which are synthesized in a proenzyme form, are activated via proteolytic cascades ([15][27]). Their activation state is tightly regulated at the transcriptional and posttranscriptional levels by multiple mechanisms. The step that is stimulated by GPCRs has not been defined. EGFR transactivation has been shown to occur primarily through shedding of HB-EGF from the membrane ([20][12], [22][28], [37][29]). Although release of other ligands for the EGFR family of receptors has been observed ([5][30], [26][31]), cleavage of pro-EGF itself has been only rarely documented. Two cases have been previously reported in which pro-EGF is cleaved to activate EGFRs ([14][32], [29][25]). The article by Chen and colleagues ([4a][1]) provides an interesting new example of this alternative pathway. ![Fig. 1.][33] Fig. 1. Scheme depicting the transactivation of epidermal growth factor receptors (EGFRs) as initiated by G protein coupled receptors (GPCRs). Note that “pro-EGF”, as used here, can refer to pro-heparin bound-EGF and other precursors to EGFR ligands, as well as the precursor to EGF itself. The proteases that are activated can be members of the matrix metalloproteinase or ADAM families. The phenomenon of EGFR transactivation has been particularly well studied in carcinoma cells, where EGFRs are commonly overexpressed ([1][34], [7][24], [35][35]). Overexpression, as well as transactivation, of EGFRs plays a prominent role in regulating tumor growth and survival. EGFR transactivation has been shown to play a potential role in cancers, such as the prostate ([20][12], [27][7]), ovarian ([22][28]), colon ([23][36]), and breast ([3][3]). Transactivation of the EGFR results in intracellular signaling that leads to growth, proliferation, and migration of cancer cells ([4][4], [6][14]). Considerable work in this regard has been done in prostate cancer cells, where ligands, including bombesin, lysophosphatidic acid, endothelin, thrombin, and carbachol can transactivate the EGFR ([27][7]). In the PC-3 human...

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