His Domain Protein Tyrosine Phosphatase and Rabaptin-5 couple endo-lysosomal sorting of EGFR with endosomal maturation

His Domain Protein Tyrosine Phosphatase (HD-PTP) collaborates with Endosomal Sorting Complexes Required for Transport (ESCRTs) to sort endosomal cargo into intralumenal vesicles, forming the multivesicular body. Completion of multivesicular body sorting is accompanied by maturation of the endosome into a late endosome, an event that requires inactivation of the early endosomal GTPase, Rab5. Here we show that HD-PTP links ESCRT function with endosomal maturation. HD-PTP depletion prevents multivesicular body sorting, whilst also blocking cargo from exiting Rab5-rich endosomes. HD-PTP depleted cells contain hyperphosphorylated Rabaptin-5, a cofactor for the Rab5 guanine nucleotide exchange factor, Rabex-5, though HD-PTP is unlikely to directly dephosphorylate Rabaptin-5. In addition, HD-PTP depleted cells exhibit Rabaptin-5 dependent hyperactivation of Rab5. HD-PTP binds directly to Rabaptin-5, between its Rabex-5 and Rab5 binding domains. This binding reaction involves the ESCRT-0/ESCRT-III binding site in HD-PTP and is competed by an ESCRT-III peptide. Jointly, these findings indicate that HD-PTP may alternately scaffold ESCRTs and modulate Rabex-5/Rabaptin-5 activity, thereby helping to coordinate the completion of MVB sorting with endosomal maturation.

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

Biochemical Society Transactions ◽

10.1042/bst20170443 ◽

2018 ◽

Vol 46 (5) ◽

pp. 1037-1046 ◽

Cited By ~ 4

Author(s):

Lydia Tabernero ◽

Philip Woodman

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Growth Factor Receptor ◽

Multivesicular Body ◽

Protein Tyrosine ◽

Epidermal Growth ◽

Domain Protein

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.

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Interaction of protein tyrosine phosphatase (PTP) 1B with its substrates is influenced by two distinct binding domains

Biochemical Journal ◽

10.1042/bj20011372 ◽

2002 ◽

Vol 364 (2) ◽

pp. 377-383 ◽

Cited By ~ 21

Author(s):

Shrikrishna DADKE ◽

Jonathan CHERNOFF

Keyword(s):

Insulin Receptor ◽

Protein Tyrosine Phosphatase ◽

Insulin Signalling ◽

Tyrosine Phosphatase ◽

Rich Region ◽

Protein Tyrosine ◽

Binding Domains ◽

C Terminus ◽

Ptp 1B ◽

Proline Rich Region

We have shown previously that protein tyrosine phosphatase (PTP) 1B interacts with insulin receptor and negatively regulates insulin signalling by an N-terminal binding domain [Dadke, Kusari and Chernoff (2000) J. Biol. Chem. 275, 23642–23647] and it also negatively regulates integrin signalling through a proline-rich region present in the C-terminus [Liu, Hill and Chernoff (1996) J. Biol. Chem. 271, 31290–31295; Liu, Sells and Chernoff (1998) Curr. Biol. 8, 173–176]. Here we show that PTP1B mutants that are defective in Src homology 3 domain binding fully retain the ability to inhibit insulin signalling, whereas mutants defective in insulin-receptor binding fully retain the ability to inhibit integrin signalling. In contrast, both the C-terminal proline-rich region and the tandem tyrosine residues present in the N-terminal region are required for the activation of Src family kinases. These data show that PTP1B can independently regulate insulin and integrin signals, and that Src might represent a convergence point for regulating signal transduction by this phosphatase.

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Conserved Mode of Interaction between Yeast Bro1 Family V Domains and YP(X) n L Motif-Containing Target Proteins

Eukaryotic Cell ◽

10.1128/ec.00091-15 ◽

2015 ◽

Vol 14 (10) ◽

pp. 976-982 ◽

Cited By ~ 7

Author(s):

Yoko Kimura ◽

Mirai Tanigawa ◽

Junko Kawawaki ◽

Kenji Takagi ◽

Tsunehiro Mizushima ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Mammalian Cells ◽

Tyrosine Phosphatase ◽

Binding Specificity ◽

Target Protein ◽

Target Proteins ◽

Protein Tyrosine ◽

Hydrophobic Groove ◽

Domain Protein ◽

Common Architecture

ABSTRACT Yeast Bro1 and Rim20 belong to a family of proteins which possess a common architecture of Bro1 and V domains. Alix and His domain protein tyrosine phosphatase (HD-PTP), mammalian Bro1 family proteins, bind YP(X) n L ( n = 1 to 3) motifs in their target proteins through their V domains. In Alix, the Phe residue, which is located in the hydrophobic groove of the V domain, is critical for binding to the YP(X) n L motif. Although the overall sequences are not highly conserved between mammalian and yeast V domains, we show that the conserved Phe residue in the yeast Bro1 V domain is important for binding to its YP(X) n L-containing target protein, Rfu1. Furthermore, we show that Rim20 binds to its target protein Rim101 through the interaction between the V domain of Rim20 and the YPIKL motif of Rim101. The mutation of either the critical Phe residue in the Rim20 V domain or the YPIKL motif of Rim101 affected the Rim20-mediated processing of Rim101. These results suggest that the interactions between V domains and YP(X) n L motif-containing proteins are conserved from yeast to mammalian cells. Moreover, the specificities of each V domain to their target protein suggest that unidentified elements determine the binding specificity.

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ESCRT-III on endosomes: new functions, new activation pathway

Biochemical Journal ◽

10.1042/bj20151115 ◽

2016 ◽

Vol 473 (2) ◽

pp. e5-e8 ◽

Cited By ~ 5

Author(s):

Philip Woodman

Keyword(s):

Mhc Class I ◽

Protein Tyrosine Phosphatase ◽

Protein Complexes ◽

Tyrosine Phosphatase ◽

Multivesicular Body ◽

Class I ◽

Recent Issue ◽

Endosomal Sorting ◽

Histocompatibility Complex ◽

Biochemical Journal

The multivesicular body (MVB) pathway sorts ubiquitinated membrane cargo to intraluminal vesicles (ILVs) within the endosome, en route to the lysosomal lumen. The pathway involves the sequential action of conserved protein complexes [endosomal sorting complexes required for transport (ESCRTs)], culminating in the activation by ESCRT-II of ESCRT-III, a membrane-sculpting complex. Although this linear pathway of ESCRT activation is widely accepted, a study by Luzio and colleagues in a recent issue of the Biochemical Journal suggests that there is greater complexity in ESCRT-III activation, at least for some MVB cargoes. They show that ubiquitin-dependent sorting of major histocompatibility complex (MHC) class I to the MVB requires the central ESCRT-III complex but does not involve either ESCRT-II or functional links between ESCRT-II and ESCRT-III. Instead, they propose that MHC class I utilizes histidine-domain protein tyrosine phosphatase (HD-PTP), a non-canonical ESCRT interactor, to promote ESCRT-III activation.

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Histidine Domain-Protein Tyrosine Phosphatase Interacts with Grb2 and GrpL

PLoS ONE ◽

10.1371/journal.pone.0014339 ◽

2010 ◽

Vol 5 (12) ◽

pp. e14339 ◽

Cited By ~ 7

Author(s):

Carmen-Alexandra Tanase

Keyword(s):

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Protein Tyrosine ◽

Domain Protein

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Mutational Analysis of the SRC Homology 2 Domain Protein-tyrosine Phosphatase Corkscrew

Journal of Biological Chemistry ◽

10.1074/jbc.273.21.13129 ◽

1998 ◽

Vol 273 (21) ◽

pp. 13129-13135 ◽

Cited By ~ 19

Author(s):

John D. Allard ◽

Ronald Herbst ◽

Pamela M. Carroll ◽

Michael A. Simon

Keyword(s):

Protein Tyrosine Phosphatase ◽

Mutational Analysis ◽

Tyrosine Phosphatase ◽

Protein Tyrosine ◽

Src Homology 2 ◽

Src Homology ◽

Domain Protein ◽

Src Homology 2 Domain

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Final Exon Frameshift Biallelic PTPN23 Variants Are Associated with Microcephalic Complex Hereditary Spastic Paraplegia

Brain Sciences ◽

10.3390/brainsci11050614 ◽

2021 ◽

Vol 11 (5) ◽

pp. 614

Author(s):

Reham Khalaf-Nazzal ◽

James Fasham ◽

Nishanka Ubeyratna ◽

David J. Evans ◽

Joseph S. Leslie ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Genetic Disorders ◽

Tyrosine Phosphatase ◽

Clinical Signs ◽

Receptor Protein ◽

Protein Tyrosine ◽

Endosomal Sorting ◽

Hereditary Spastic Paraplegias ◽

Gene Testing ◽

Escrt Complex

The hereditary spastic paraplegias (HSPs) are a large clinically heterogeneous group of genetic disorders classified as ‘pure’ when the cardinal feature of progressive lower limb spasticity and weakness occurs in isolation and ‘complex’ when associated with other clinical signs. Here, we identify a homozygous frameshift alteration occurring in the last coding exon of the protein tyrosine phosphatase type 23 (PTPN23) gene in an extended Palestinian family associated with autosomal recessive complex HSP. PTPN23 encodes a catalytically inert non-receptor protein tyrosine phosphatase that has been proposed to interact with the endosomal sorting complex required for transport (ESCRT) complex, involved in the sorting of ubiquitinated cargos for fusion with lysosomes. In view of our data, we reviewed previously published candidate pathogenic PTPN23 variants to clarify clinical outcomes associated with pathogenic gene variants. This determined that a number of previously proposed candidate PTPN23 alterations are likely benign and revealed that pathogenic biallelic PTPN23 alterations cause a varied clinical spectrum comprising of complex HSP associated with microcephaly, which may occur without intellectual impairment or involve more severe neurological disease. Together, these findings highlight the importance of the inclusion of the PTPN23 gene on HSP gene testing panels globally.

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