Determination of EGFR Signaling Output by Opposing Gradients of BMP and JAK/STAT Activity

Abstract

A relatively small number of signaling pathways drive a wide range of developmental decisions, but how this versatility in signaling outcome is generated is not clear. In the Drosophila follicular epithelium, localized epidermal growth factor receptor (EGFR) activation induces distinct cell fates depending on its location. Posterior follicle cells respond to EGFR activity by expressing the T-box transcription factors Midline and H15, while anterior cells respond by expressing the homeodomain transcription factor Mirror. We show that the choice between these alternative outputs of EGFR signaling is regulated by antiparallel gradients of JAK/STAT and BMP pathway activity and that mutual repression between Midline/H15 and Mirror generates a bistable switch that toggles between alternative EGFR signaling outcomes. JAK/STAT and BMP pathway input is integrated through their joint and opposing regulation of both sides of this switch. By converting this positional information into a binary decision between EGFR signaling outcomes, this regulatory network ultimately allows the same ligand-receptor pair to establish both the anterior-posterior (AP) and dorsal-ventral (DV) axes of the tissue.

Epithelial Patterning, Morphogenesis, and Evolution: Drosophila Eggshell as a Model

“…Regarding the latter question, one difference in these signaling events is that early processes require only low levels of Grk signaling, while later processes involve higher levels of ligand; that is, weak loss-of- function mutations do not affect posterior patterning, only dorsal patterning (Schüpbach, 1987). In addition, a recent study demonstrates that the different consequences of Grk signaling in the dorsal-anterior versus the posterior follicle cells is due to the cooperative action of Grk with two additional signaling pathways: the Dpp pathway, which is activated in the anterior as discussed above, and the JAK/STAT pathway, which is activated by the ligand Unpaired in the posterior (Fregoso Lomas et al, 2016). Signaling by Grk and Dpp together results in expression of Mirror (Mirr), a dorsal fate determinant discussed below.…”

“…Signaling by Grk and JAK/STAT together results in expression of Mid and H15. Furthermore, Mid/H15 and Mirr mutually repress each other, potentially allowing for a switch-like response between the anterior and posterior interpretations of the Grk signal (Fregoso Lomas et al, 2016). …”

A Gene Expression Screen inDrosophila melanogasterIdentifies Novel JAK/STAT and EGFR Targets During Oogenesis

“…To activate EGFR signaling in the FCs, we expressed a dominant active EGFR using UAS-λtop (Queenan et al 1997). Previous work has shown that ectopic expression of these two signaling components is sufficient to convert AFCs and main body follicle cells into PFCs (Fregoso Lomas et al 2016). However, to confirm that this was the case, we stained control and ectopic expression egg chambers using an antibody against Midline (Mid), which is expressed specifically in the PFCs (Fregoso Lomas et al 2013; Figure 2A).…”

“…Together, JAK/STAT and EGFR activity produce the posterior follicle cell (PFC) fate (Xi et al 2003). Previous work has demonstrated that by removing JAK/STAT or EGFR it is possible to disrupt PFC formation, and that ectopic activity of both pathways in the follicle cells can induce ectopic PFCs (Xi et al 2003; Fregoso Lomas et al 2016). In the Drosophila egg chamber, EGFR signaling activates the conserved MAPK/ERK signaling cascade (Schnorr and Berg 1996); consequently, disrupting the components of this cascade can also interfere with PFC specification.…”

Advances in Targeting the Epidermal Growth Factor Receptor Pathway by Synthetic Products and Its Regulation by Epigenetic Modulators as a Therapy for Glioblastoma

“…Epidermal growth factor receptor (EGFR) is a transmembrane protein involved in a broad range of developmental processes and human cancers, including glioblastoma, neck and head cancer, colorectal cancer, and non-small-cell lung cancer [9,10,11]. It has been shown that 40–50% of glioblastoma patients have dysregulated EGFR, and approximately half of these co-express the mutant receptor EGFR variant III (EGFRvIII) [12].…”