Dissecting the role of His domain protein tyrosine phosphatase/PTPN23 and ESCRTs in sorting activated epidermal growth factor receptor to the multivesicular body

Abstract

Sorting of activated epidermal growth factor receptor (EGFR) into intraluminal vesicles (ILVs) within the multivesicular body (MVB) is an essential step during the down-regulation of the receptor. The machinery that drives EGFR sorting attaches to the cytoplasmic face of the endosome and generates vesicles that bud into the endosome lumen, but somehow escapes encapsulation itself. This machinery is termed the ESCRT (endosomal sorting complexes required for transport) pathway, a series of multi-protein complexes and accessory factors first identified in yeast. Here, we review the yeast ESCRT pathway and describe the corresponding components in mammalian cells that sort EGFR. One of these is His domain protein tyrosine phosphatase (HD-PTP/PTPN23), and we review the interactions involving HD-PTP and ESCRTs. Finally, we describe a working model for how this ESCRT pathway might overcome the intrinsic topographical problem of EGFR sorting to the MVB lumen.

PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors

“…2), which, together with the Bro domain, plays a central role in EGFR downregulation and formation of intraluminal vesicles in MVBs (Doyotte et al, 2008;Tabernero and Woodman, 2018). These domains are structurally related to those found in Alix, which is required for ESCRT function (Tabernero and Woodman, 2018). Therefore, the association of BICD1 with the V/CC domain of PTPN23 further supports a direct role of BICD1 in NTR sorting (Terenzio et al, 2014a).…”

“…Linking PTPN23 and BICD1 to endocytic sorting of NTRs is mechanistically challenging in light of the functional heterogeneity of signalling endosomes (Villarroel-Campos et al, 2018) and the emerging differences in how this process is regulated in post-mitotic neurons versus proliferating cells. Although further work is necessary to fully characterise the PTPN23-KD phenotype described here, the role of PTPN23 in intracellular cargo sorting is somewhat easier to interpret than how BICD1 performs this function, primarily due to the extensive literature focussed on the characterisation of PTPN23 in EGFR dynamics (Woodman, 2016;Gahloth et al, 2016Gahloth et al, , 2017Tabernero and Woodman, 2018). Interestingly, PTPN23 binds endophilin A1 (Ichioka et al, 2007), which is involved in the endocytic sorting of TrkB (Burk et al, 2017).…”

“…BICD1 directly binds the V/CC domain of PTPN23 (Fig. 2), which, together with the Bro domain, plays a central role in EGFR downregulation and formation of intraluminal vesicles in MVBs (Doyotte et al, 2008;Tabernero and Woodman, 2018). These domains are structurally related to those found in Alix, which is required for ESCRT function (Tabernero and Woodman, 2018).…”

“…To further our understanding of the BICD1-dependent sorting mechanism, we characterised the BICD1 interactome using a proteomic approach, and identified protein tyrosine phosphatase, non-receptor type 23 (PTPN23; or histidine domain-containing protein tyrosine phosphatase, HD-PTP), a member of the endosomal sorting complexes required for transport (ESCRT) machinery (Tabernero and Woodman, 2018) as a BICD1 binding partner. PTPN23 directs the molecular sorting of several transmembrane receptors, such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) in non-neuronal cells (Doyotte et al, 2008;Ma et al, 2015).…”

Phenotype and mutation expansion of the PTPN23 associated disorder characterized by neurodevelopmental delay and structural brain abnormalities

“…PTPN23 encodes the 1636 amino acid non-receptor protein tyrosine phosphatase type 23 that appears to be essential for endocytic trafficking. It interacts with ESCRT (endosomal sorting complex required for transport) complexes to sort ubiquitinated proteins into multi-vesicular bodies (MVBs) [5, 6]. Depletion of the protein has been shown to cause accumulation of ubiquitinated proteins in the endosomes and disrupt the morphogenesis of MVBs [6].…”