Branch-restricted localization of phosphatase Prl-1 specifies axonal synaptogenesis domains

Urwyler, Olivier; Izadifar, Azadeh; Vandenbogaerde, Sofie; Sachse, Sonja; Misbaer, Anke; Schmucker, Dietmar

doi:10.1126/science.aau9952

Cited by 39 publications

(48 citation statements)

References 63 publications

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“…Fig 5), whereas inhibition of ezrin function by the small molecule compound NSC668394 caused more and larger blebs to form (Supp Fig 6). Additionally, the recent finding that knockout of a different phosphatase with activity for ezrin decreases protrusion in neurons in vivo supports the role of ezrin dephosphorylation in protrusion initiation (26). Compared to cells expressing wildtype ezrin, osteosarcoma cells expressing the T567D mutant exhibit fewer protrusions (Fig.…”

supporting

confidence: 53%

A unified role for membrane-cortex detachment during cell protrusion initiation

Welf

Miles

Huh

et al. 2019

Preprint

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Cell morphogenesis employs a diversity of membrane protrusions. They are discriminated by differences in force generation. Actin polymerization is the best studied mechanism of force generation, but growing interest in how variable molecular conditions and microenvironments alter morphogenesis has revealed other mechanisms, including intracellular pressure. Here, we show that local depletion of membrane cortex links is an essential step in the initiation of both pressure-based and actin-based protrusions. This observation challenges the quarter-century old Brownian ratchet model of actin-driven membrane protrusion, which requires an optimal balance of actin filament growth and membrane tethering. An updated model confirms membrane-filament detachment is necessary to activate the ratchet mechanism. These findings unify the regulation of different protrusion types, explaining how cells generate robust yet flexible strategies of morphogenesis. Main textCells use several mechanisms to generate the force required for membrane protrusion, with the choice of mechanism depending on cell-autonomous and environmental factors. High resolution microscopy of the molecular dynamics underlying these processes has until recently only been possible on cells adhering to glass coverslips. As a result, the most widely studied type of protrusions are the broad, flat lamellipodia that form in highly adherent cells (1). Lamellipodial protrusions are driven by actin polymerization against the plasma membrane. The persistence of this process varies widely between cell types, from tens of seconds to minutes, dependent on the efficiency of regulatory processes that upregulate the rate of monomer incorporation into the filamentous actin (f-actin) network against the resistance of the plasma membrane and the coupling of the network to substrate-anchored adhesions (2). In contrast, cells in more complex microenvironments often exhibit rounded protrusions, sometimes referred to as blebs, which are driven by intracellular pressure. Blebs form via separation of the plasma membrane from the actin cortex during a rapid expansion and typically persist for approximately 30 seconds before onset of a retraction phase that is characterized by recruitment of ezrin-radixin-moesin (ERM) family proteins and reassembly of an actin cortex (3,4). Perturbation of ERM proteins affects bleb size and frequency as well as bleb-driven migration in vivo (5,6), but this result is often ascribed to perturbations of the roles ERM proteins play in generating intracellular pressure (7,8). Other recently described protrusion mechanisms are hybrids between actin-and pressure driven mechanisms (9-11). The purely actin-driven lamellipodia and pressure-driven blebs thus represent the archetypical extremes of a wide protrusion spectrum. Especially in the context of cancer, the plasticity between lamellipodia-driven, mesenchymal migration and bleb-driven, amoeboid migration is a powerful mechanism for metastatic cells to navigate highly variable microenvironments (12). However,...

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supporting

confidence: 53%

A unified role for membrane-cortex detachment during cell protrusion initiation

Welf

Miles

Huh

et al. 2019

Preprint

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“…Decreased gene expressions of Ptp4a1 along with other cAMP response element‐binding protein (CREB)‐dependent genes were seen in the hippocampus of trained APP Sw,Ind mice, which were associated with early memory loss [16]. Further evidence demonstrated that PTP4A1 (also known as phosphatase of regenerating liver‐1) was important for synapse formation via modulation of insulin receptor‐Akt signaling in Drosophila ; loss of phosphatase of regenerating liver‐1 resulted in locomotor deficiencies and decreased numbers of synapses [17]. Therefore, dysregulation of PTP4A1 may directly cause the loss of synapses leading to the memory loss characteristic of AD dementia.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel candidate autoantibodies in Alzheimer’s disease

Wang

Zailan

Wong

et al. 2020

Euro J of Neurology

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Background and purpose: Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, it is unknown whether autoantibodies are upregulated in amyloid-tau biomarker-confirmed AD. Methods: A total of 40 subjects with mild dementia (Clinical Dementia Rating = 1) were stratified into AD (n = 16) and non-AD (n = 24) groups according to their cerebrospinal fluid levels of tau and Ab 42. Their sera were collected and analyzed using a microarray containing > 1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method with the following criteria: penetrance fold change (AD) ≥ 2, frequency (AD) ≥ 15% and frequency (non-AD) = 0%. Results: All controls and samples passed the quality control criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: nucleosome assembly protein 1-like 3 (31.3%, 5/16 subjects) and microtubule-associated protein 4, pantothenic acid kinase 3, phosphoinositide-3-kinase regulatory subunit 1, protein tyrosine phosphatase type IVA member 1 and SRY (sex-determining region Y)-box 15 (all 18.8%, 3/16 subjects). Conclusions: Although some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.

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“…Intracellular regulation may involve protein interaction or posttranslational modifications or local protein translation at the rear of a migrating cell. In line with local translation, the Drosophila axonal synaptogenesis domains are specified by branch-restricted localization of the membrane-anchored phosphatase of regenerating liver (Prl-1), and the spatial restriction of Prl-1 requires untranslated sequences in its messenger RNA (32).…”

Section: Discussionmentioning

confidence: 99%

Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration

Zhu

Chai

et al. 2020

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

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Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration inCaenorhabditis elegans, the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1–dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells.

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Branch-restricted localization of phosphatase Prl-1 specifies axonal synaptogenesis domains

Cited by 39 publications

References 63 publications

A unified role for membrane-cortex detachment during cell protrusion initiation

A unified role for membrane-cortex detachment during cell protrusion initiation

Identification of novel candidate autoantibodies in Alzheimer’s disease

Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration

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