Myopic acts in the endocytic pathway to enhance signaling by theDrosophilaEGF receptor

Abstract

Endocytosis of activated receptors can control signaling levels by exposing the receptors to novel downstream molecules or by instigating their degradation. Epidermal growth factor receptor (EGFR) signaling has crucial roles in development and is misregulated in many cancers. We report here that Myopic, the Drosophila homolog of the Bro1-domain tyrosine phosphatase HD-PTP, promotes EGFR signaling in vivo and in cultured cells. myopic is not required in the presence of activated Ras or in the absence of the ubiquitin ligase Cbl, indicating that it acts on internalized EGFR, and its overexpression enhances the activity of an activated form of EGFR. Myopic is localized to intracellular vesicles adjacent to Rab5-containing early endosomes, and its absence results in the enlargement of endosomal compartments. Loss of Myopic prevents cleavage of the EGFR cytoplasmic domain, a process controlled by the endocytic regulators Cbl and Sprouty. We suggest that Myopic promotes EGFR signaling by mediating its progression through the endocytic pathway. KEY WORDS: ESCRT complex, MAP kinase, HD-PTP (PTPN23), Bro1 domain, Photoreceptor

Expression analysis and essential role of the putative tyrosine phosphatase His-domain-containing protein tyrosine phosphatase (HD-PTP)

“…The specificity of HD-PTP expression in epithelia suggests that it could be involved in signaling pathways activated in epithelial cells. Consistently, a role for HD-PTP in the endosomal transport of the EGF receptor, which is highly expressed in tissues from epithelial and neuronal origins, and resulting in the enhancement of its downstream signaling has recently been described (Miura et al, 2008).…”

“…The HD-PTP protein encompasses four main domains: a functionally uncharacterized BRO1-like domain (BRO), a histidine-rich domain (HIS), a classical protein tyrosine phosphatase domain (PTP) and a proteolytic degradation targeting sequence (PEST motif) (Toyooka et al, 2000). Potential functions for HD-PTP in inhibition of endothelial migration and EGFR endosomal trafficking were recently reported, but its role in vivo is still undefined (Castiglioni et al, 2007;Doyotte et al, 2008;Mariotti et al, 2008;Miura et al, 2008). The high level of conservation of HD-PTP among multi-cellular organisms (human, monkey, mouse, rat, chicken, frog and fly) suggests a significant and common biological function, as does its ubiquitous mRNA expression in adult human and rat organs (Cao et al, 1998;Mariotti et al, 2006).…”

Drosophila Vps4 promotes Epidermal growth factor receptor signaling independently of its role in receptor degradation

“…Blocking EGFR internalization by removing Dynamin prevents its degradation, enhancing some downstream signaling events, but other aspects of EGFR signal transduction require an endosomal localization for the receptor (Jones and Rappoport, 2014;Legent et al, 2012;Miura et al, 2008;Teis et al, 2006;Vieira et al, 1996). Internalized EGFR can be either degraded or recycled to the plasma membrane, a choice that depends on the concentration and nature of the ligand, as ligands that remain bound in acidic late endosomes promote more extensive receptor ubiquitylation (Eden et al, 2012;French et al, 1995;Roepstorff et al, 2009;Sigismund et al, 2005).…”

“…However, the transcriptional response in cultured mammalian cells depends primarily on EGFR activity at the plasma membrane (Brankatschk et al, 2012;Sousa et al, 2012). Observed effects on EGFR signaling could vary depending both on the stage at which endocytic sorting is blocked and the cellular context examined (Babst et al, 2000;Bache et al, 2006;Chanut-Delalande et al, 2010;Lloyd et al, 2002;Miura et al, 2008). …”

Regulation of Toll and Toll-like receptor signaling by the endocytic pathway

“…[18][19][20] Interestingly, both Hrs and Mop, as well as components of the downstream ESCRT I complex are also necessary for proper Drosophila EGFR signaling in imaginal disc patterning and cell culture. 21,22 Miura et al further demonstrate that receptor progression from early to late endosomes has a positive effect on EGFR signaling and that the absence of Hrs or Mop disrupts this process. However, the positive role of Hrs and the ESCRT machinery in Drosophila EGFR signaling is by no means universal, as Hrs appears to promote EGFR downregulation in early embryonic development.…”