Receptor tyrosine kinases in Drosophila development

Abstract

Tyrosine phosphorylation plays a significant role in a wide range of cellular processes. The Drosophila genome encodes more than 20 receptor tyrosine kinases and extensive studies in the past 20 years have illustrated their diverse roles and complex signaling mechanisms. Although some receptor tyrosine kinases have highly specific functions, others strikingly are used in rather ubiquitous manners. Receptor tyrosine kinases regulate a broad expanse of processes, ranging from cell survival and proliferation to differentiation and patterning. Remarkably, different receptor tyrosine kinases share many of the same effectors and their hierarchical organization is retained in disparate biological contexts. In this comprehensive review, we summarize what is known regarding each receptor tyrosine kinase during Drosophila development. Astonishingly, very little is known for approximately half of all Drosophila receptor tyrosine kinases.

Figure 1.

Torso activation in embryogenesis. Processing of the Torso ligand Trunk occurs locally at the anterior and posterior embryonic poles and requires Torso-like, fs(1)N, and fs(1)ph. Engagement of Torso by processed Trunk triggers Torso autophosphorylation and subsequent recruitment of downstream adaptors and effectors. A phosphorylation cascade initiated by Tor activation and involving Raf/Phl, Mek/Dsor1, and ERK/Rl leads to the inhibition of transcriptional repression by Cic and Gro. This permits gap gene (tailless and huckebein) and subsequent pair-rule gene expression and enables patterning of the developing embryo.

Figure 2.

Sevenless and EGFR signaling in photoreceptor specification. Engagement of Sev on the R7 photoreceptor cell by its ligand Boss on R8 activates the Ras/Raf/Mek/ERK signaling cascade in R7. A similar cassette of signaling proteins execute EGFR-dependent functions, following EGFR activation by its ligand Spitz. Sev activation in R8 is prevented by Socs36E and reinforced in R7 by the adaptor protein Drk, whereas Argos and Kekkon limit EGFR activation. Phosphorylated and active ERK/Rl targets the transcriptional repressors Aop and Ttk (via Phyl-Sina-Ebi) for degradation, whereas ERK-dependent phosphorylation stimulates Pnt transcriptional activity. This relieves transcriptional repression at lozenge and prospero enhancers. Lz functions together with Pnt to activate pros expression, thus providing R7 identity by repressing the expression of cone cell and R8-specific rhodopsins.

Figure 3.

Breathless signaling in the tracheal system. Btl autophosphorylation, on Bnl binding, recruits the adaptor protein Stumps and additional downstream effectors. Ras activation initiates a phosphorylation cascade that culminates in the stimulation of ERK kinase activity. ERK-dependent phosphorylation of the transcriptional activators Grh and Pnt, and the transcriptional repressors Gro and Aop, modulates their activity at promoters. The consequential up-regulation of gene expression induces tracheal cell migration and tracheal branching and fine-tuning of Btl signaling.

Figure 4.

Ubiquitous InR signaling. Interaction of InR with its Ilp ligand induces InR autophosphorylation. Chico interacts directly with the phosphorylated receptor, recruiting PI3K along with a multitude of other factors including adaptor proteins and downstream effectors. InR promotes proliferation via canonical Ras/Raf/Mek/ERK signaling and growth via the activation of Akt1. Akt1 stimulates protein synthesis by activating downstream kinases Tor and S6K, and by inhibiting Foxo nuclear accumulation and transcriptional activity.