Receptor tyrosine phosphatases control tracheal tube geometries through negative regulation of Egfr signaling

Abstract

The formation of epithelial tubes with defined shapes and sizes is essential for organ development. We describe a unique tracheal tubulogenesis phenotype caused by loss of both Drosophila type III receptor tyrosine phosphatases (RPTPs), Ptp4E and Ptp10D. Ptp4E is the only widely expressed Drosophila RPTP, and is the last of the six fly RPTPs to be genetically characterized. We recently isolated mutations in Ptp4E, and discovered that, although Ptp4E null mutants have no detectable phenotypes, double mutants lacking both Ptp4E and Ptp10D display synthetic lethality at hatching owing to respiratory failure. In these double mutants, unicellular and terminal tracheal branches develop large bubble-like cysts that selectively incorporate apical cell surface markers. Cysts in unicellular branches are enlargements of the lumen that are sealed by adherens junctions, whereas cysts in terminal branches are cytoplasmic vacuoles. Cyst size and number are increased by tracheal expression of activated Egfr tyrosine kinase, and decreased by reducing Egfr levels. Ptp10D forms a complex with Egfr in transfected cells. Downregulation of Egfr signaling by the RPTPs is required for the construction of tubular lumens, whether extracellular or intracellular, by cells that undergo remodeling during branch morphogenesis. The Ptp4E Ptp10D phenotype represents the first evidence of an essential role for RPTPs in epithelial organ development. These findings might be relevant to organ development and disease in mammals, because PTPRJ (DEP-1), an ortholog of Ptp4E/Ptp10D, interacts with the hepatocyte growth factor receptor tyrosine kinase. PTPRJ corresponds to the murine Scc1 (suppressor of colon cancer) gene.

Identification of ptpro as a novel target gene of Wnt signaling and its potential role as a receptor for Wnt

“…PTPRO may inhibit Wnt signaling not only by sequestration of Wnt ligand but also by regulation of other Wnt signaling components. For example, Drosophila homolog of PTPRO, ptp4e or ptp10d, plays an inhibitory role in EGF signaling by genetically interacting with epidermal growth factor receptor (EGFR) [25]. It may be possible that activation of PTPRO by binding with Wnt regulates EGF signaling as well.…”

R3 receptor tyrosine phosphatases: Conserved regulators of receptor tyrosine kinase signaling and tubular organ development

“…Drosophila Ptp10D binds to EGFR (Jeon and Zinn, 2009) as does nematode DEP-1(Berset et al, 2005). Thus, interactions between R3 RPTPs and EGFR are conserved between vertebrates and invertebrates.…”

“…Thus, interactions between R3 RPTPs and EGFR are conserved between vertebrates and invertebrates. The Drosophila R3 RPTPs also negatively regulate signaling by the FGFR and PDGFR/VEGFR orthologs, known as Breathless (Btl) and Pvr, but have not been shown to physically interact with them (Jeon et al, 2012; Jeon and Zinn, 2009b). …”

“…Ptp10D is the ancestral gene, being present in all insects, while Ptp4E is the result of a recent gene duplication(Jeon et al, 2008b). Ptp4E and Ptp10D single mutants are viable and fertile, but Ptp4E Ptp10D double mutants die from respiratory failure at the end of embryogenesis(Jeon and Zinn, 2009a). Ptp4E Ptp10D double mutants have defects in lumen formation that are specific to unicellular tubes and tracheoles; multicellular tubes are unaffected.…”

Mechanisms of Lumen Development in Drosophila Tubular Organs

“…In embryos double mutant for two receptor-linked protein-tyrosine phosphatases (RPTPs), Ptp4E and Ptp10D, tracheal branches, such as the ganglionic branches and terminal branches, form large bubble-like cysts with dilated lumens that stain positive for apical marker proteins (Jeon and Zinn, 2009). Cyst size and number are increased upon expression of activated Egfr (epidermal growth factor receptor) and decreased with reduction of Egfr.…”