The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function

Gahloth, Deepankar; Heaven, Graham; Jowitt, Thomas A.; Mould, A. Paul; Bella, Jordi; Baldock, Clair; Woodman, Philip; Tabernero, Lydia

doi:10.1038/s41598-017-09467-9

Cited by 23 publications

(40 citation statements)

References 57 publications

(111 reference statements)

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“…Indeed, this is a defining characteristic of scaffold proteins (24,25). Given that Myopic interacts with several functionally unrelated proteins (9,10,26), our results are consistent with a Myopic complex governing release by DCVs, but not SSVs. However, a Myopic mutant shows that regulation of neuropeptide release is not mediated by Myopic association with the ESCRT III protein Shrub (CHMP4), which is required for Myopic's effect on neuron pruning (12).…”

Section: Discussionsupporting

confidence: 82%

Myopic (HD-PTP, PTPN23) selectively regulates synaptic neuropeptide release

Bulgari

Jha

Deitcher

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransmission is mediated by synaptic exocytosis of neuropeptide-containing dense-core vesicles (DCVs) and small-molecule transmitter-containing small synaptic vesicles (SSVs). Exocytosis of both vesicle types depends on Ca and shared secretory proteins. Here, we show that increasing or decreasing expression of Myopic (mop, HD-PTP, PTPN23), a Bro1 domain-containing pseudophosphatase implicated in neuronal development and neuropeptide gene expression, increases synaptic neuropeptide stores at the neuromuscular junction (NMJ). This occurs without altering DCV content or transport, but synaptic DCV number and age are increased. The effect on synaptic neuropeptide stores is accounted for by inhibition of activity-induced Ca-dependent neuropeptide release. cAMP-evoked Ca-independent synaptic neuropeptide release also requires optimal Myopic expression, showing that Myopic affects the DCV secretory machinery shared by cAMP and Ca pathways. Presynaptic Myopic is abundant at early endosomes, but interaction with the endosomal sorting complex required for transport III (ESCRT III) protein (CHMP4/Shrub) that mediates Myopic's effect on neuron pruning is not required for control of neuropeptide release. Remarkably, in contrast to the effect on DCVs, Myopic does not affect release from SSVs. Therefore, Myopic selectively regulates synaptic DCV exocytosis that mediates peptidergic transmission at the NMJ.

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Section: Discussionsupporting

confidence: 82%

Myopic (HD-PTP, PTPN23) selectively regulates synaptic neuropeptide release

Bulgari

Jha

Deitcher

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…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).…”

Section: Discussionmentioning

confidence: 98%

“…Among the highest ranked hits (Table 1), we selected the tumour suppressor PTPN23 (Manteghi et al, 2016;Gingras et al, 2017) for follow-up analyses based on its established role in endosomal sorting (Doyotte et al, 2008). In non-neuronal cells, PTPN23 directly regulates the function of the ESCRT machinery, which controls the biogenesis of multivesicular bodies (MVBs) and their cargo degradation in lysosomes (Ali et al, 2013;Lee et al, 2016;Woodman, 2016;Gahloth et al, 2017). Importantly, acute downregulation of PTPN23 in HeLa cells (Doyotte et al, 2008) and of BICD1 in ES-MNs (Terenzio et al, 2014a) results in a very similar phenotype, characterised by the accumulation of activated growth factor receptors in enlarged endocytic compartments, thus suggesting that PTPN23 and BICD1 regulate sorting of activated NTRs in neurons.…”

Section: Investigating the Bicd1 Interactome During Endocytic Sortingmentioning

confidence: 99%

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

Budzinska

Villarroel‐Campos

Golding

et al. 2020

Journal of Cell Science

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Signalling by target-derived neurotrophins is essential for the correct development of the nervous system and its maintenance throughout life. Several aspects concerning the lifecycle of neurotrophins and their receptors have been characterised over the years, including the formation, endocytosis and trafficking of signalling-competent ligandreceptor complexes. However, the molecular mechanisms directing the sorting of activated neurotrophin receptors are still elusive. Previously, our laboratory identified Bicaudal-D1 (BICD1), a dynein motor adaptor, as a key factor for lysosomal degradation of brain-derived neurotrophic factor (BDNF)-activated TrkB (also known as NTRK2) and p75 NTR (also known as NGFR) in motor neurons. Here, using a proteomics approach, we identified protein tyrosine phosphatase, non-receptor type 23 (PTPN23), a member of the endosomal sorting complexes required for transport (ESCRT) machinery, in the BICD1 interactome. Molecular mapping revealed that PTPN23 is not a canonical BICD1 cargo; instead, PTPN23 binds the N-terminus of BICD1, which is also essential for the recruitment of cytoplasmic dynein. In line with the BICD1-knockdown phenotype, loss of PTPN23 leads to increased accumulation of BDNF-activated p75 NTR and TrkB in swollen vacuolelike compartments, suggesting that neuronal PTPN23 is a novel regulator of the endocytic sorting of neurotrophin receptors.

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“…It has been shown that PTPN23 is essential during embryonic development, and its expression in adult mice is limited to the epithelium of multiple organs including the epithelium of the stomach, small intestine, and colon [20]. PTPN23 encodes for the protein HD-PTP, which controls cell migration and endocytosis [21]. The role of PTPN23 in IECs in the intestine has not been studied yet.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Protein Tyrosine Phosphatase Nonreceptor Type 2 in Intestinal Epithelial Cells Results in Upregulation of the Related Phosphatase Protein Tyrosine Phosphatase Nonreceptor Type 23

et al. 2019

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Background/Aims: Knockdown of protein tyrosine phosphatase nonreceptor type 2 (PTPN2) exaggerates IFN-γ-induced intestinal barrier defects, but mice constitutively lacking PTPN2 in epithelial cells (PTPN2xVilCre mice) do not show changes in epithelial function or enhanced susceptibility to experimental colitis. Here, we investigated whether PTPN2 modulates the expression of related tyrosine phosphatases. Methods: PTPN2 knockdown in HT-29 cells was induced using siRNA constructs. Acute colitis in PTPN2xVilCre mice was induced by 2% dextran sulfate sodium (DSS) in drinking water for 7 days. Colitis-associated tumors were induced by injection of azoxymethane prior to treatment with DSS for 3 consecutive cycles. Results: In HT-29 cells, PTPN2 depletion resulted in enhanced mRNA expression of PTPN11 and PTPN23 and in parallel to upregulation of IL-18 mRNA upon treatment with TNF for 24 h. DSS treatment of PTPN2-deficient mice resulted in a strong induction of Ptpn23 mRNA in colon tissue in vivo. In the tumor model, Ptpn23 mRNA was again clearly upregulated in nontumor tissue from PTPN2-deficient mice; however, this was not observed in tumor tissue. Conclusions: Our experiments show that PTPN23 function might, at least partially, compensate lack of PTPN2 in epithelial cells. Upregulation of PTPN23 might therefore crucially contribute to the lack of a colitis phenotype in PTPN2-VilCre mice.

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The open architecture of HD-PTP phosphatase provides new insights into the mechanism of regulation of ESCRT function

Cited by 23 publications

References 57 publications

Myopic (HD-PTP, PTPN23) selectively regulates synaptic neuropeptide release

Myopic (HD-PTP, PTPN23) selectively regulates synaptic neuropeptide release

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

Deletion of Protein Tyrosine Phosphatase Nonreceptor Type 2 in Intestinal Epithelial Cells Results in Upregulation of the Related Phosphatase Protein Tyrosine Phosphatase Nonreceptor Type 23

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