Plasma membrane phospholipid phosphatase-related proteins as pleiotropic regulators of neuron growth and excitability

Fuchs, Joachim; Bareesel, Shannon; Kroon, Cristina; Polyzou, Alexandra; Eickholt, Britta J.; Leondaritis, George

doi:10.3389/fnmol.2022.984655

Cited by 7 publications

(7 citation statements)

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“…The intracellular region of PLPPR3, as well as other PLPPRs, likely mediates the filopodia formation function as well as protein-protein interactions. [1][2][3][9][10][11][12] However, the regulation of PLPPR3 by post-translational modifications is currently not understood. We tested the presence of phosphorylation, the most pervasive and well-understood post-translational modification, in primary cortical neurons at DIV9, when PLPPR3 expression peaks in culture.…”

Section: Resultsmentioning

confidence: 99%

“…PLPPR3 phospho-mutants showed equivalent plasma membrane localization with the WT protein, which is considered a requisite of PLPPR-induced filopodia formation. 1 However, there were no differences in filopodia density between the phosphomutants and the WT (Figure 3H, I). Thus, we concluded that phosphorylation of PLPPR3 S351 does not regulate filopodia formation.…”

Section: Plppr3 S351 Is a Pka Phosphorylation Sitementioning

confidence: 89%

“…The first phosphorylation cluster overlaps with the region of hydrophobic and positively charged amino acids (aa 341-352 in PLPPR3), while the second phosphorylation cluster overlaps with a region of phosphorylatable and negatively charged residues (aa 555-567). 1 Thus, these regions could be important regulatory domains in all PLPPRs.…”

Section: The Intracellular Domain Of Plppr3 Is Highly Phosphorylatedmentioning

confidence: 99%

“…Phospholipid phosphatase-related protein 3 (PLPPR3), previously also known as plasticity-related gene 2 (PRG2), belongs to a family of membrane proteins (PLPPR1-5) with described functions in neuronal growth and synaptic transmission. 1 All PLPPRs share highly conserved six transmembrane domains, and much less conserved intracellular domains of various lengths. This topology makes them ideally suited to integrate cell extrinsic and cell intrinsic signals involved in orchestrating growth and plasticity.…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

Kroon,

Bareesel,

Kirchner

et al. 2024

Preprint

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Phospholipid–phosphatase related protein 3 (PLPPR3, previously known as Plasticity Related Gene 2 or PRG2) belongs to a family of transmembrane proteins, highly expressed in neuronal development, which regulate critical growth processes in neurons. Prior work established crucial functions of PLPPR3 in axon guidance, filopodia formation and axon branching. However, little is known regarding the signaling events regulating PLPPR3 function. We identify here 26 high–confidence phosphorylation sites in the intracellular domain of PLPPR3 using mass spectrometry. Biochemical characterization established one of these — S351 — as a bona fide phosphorylation site of PKA. Experiments in neuronal cell lines suggest that phosphorylation of S351 does not regulate filopodia formation. Instead, it regulates binding to BASP1, a signaling molecule previously implicated in axonal growth and regeneration. Interestingly, both PLPPR3 intracellular domain and BASP1 enrich in presynapses in primary neurons. We propose that the presynaptic PLPPR3-BASP1 complex may function as novel signaling integrator at neuronal synapses.

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Section: Resultsmentioning

confidence: 99%

Section: Plppr3 S351 Is a Pka Phosphorylation Sitementioning

confidence: 89%

Section: The Intracellular Domain Of Plppr3 Is Highly Phosphorylatedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

Kroon,

Bareesel,

Kirchner

et al. 2024

Preprint

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“…PRG3 and PRG5 belong to the family of plasticity-related genes (PRGs), which defines a subclass of the Lipid Phosphate Phosphatase (LPP) superfamily. The PRG family comprises five, vertebrate, brain-specific membrane proteins, which influence lipid phosphate signaling and thereby promote filopodia formation, neurite extension, axonal sprouting and reorganization after lesions [ 7 , 8 , 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Although PRG3 and PRG5 share the highest structural and sequence similarities within the PRG family, their short (~50 amino acids) intracellularly located C-termini are unique [ 16 , 18 ], which indicates that they might exert different functions in cells compared to each other.…”

Section: Introductionmentioning

confidence: 99%

PRG3 and PRG5 C-Termini: Important Players in Early Neuronal Differentiation

Brandt

Willmer

Ayon-Olivas

et al. 2022

IJMS

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The functional importance of neuronal differentiation of the transmembrane proteins’ plasticity-related genes 3 (PRG3) and 5 (PRG5) has been shown. Although their sequence is closely related, they promote different morphological changes in neurons. PRG3 was shown to promote neuritogenesis in primary neurons; PRG5 contributes to spine induction in immature neurons and the regulation of spine density and morphology in mature neurons. Both exhibit intracellularly located C-termini of less than 50 amino acids. Varying C-termini suggested that these domains shape neuronal morphology differently. We generated mutant EGFP-fusion proteins in which the C-termini were either swapped between PRG3 and PRG5, deleted, or fused to another family member, plasticity-related gene 4 (PRG4), that was recently shown to be expressed in different brain regions. We subsequently analyzed the influence of overexpression in immature neurons. Our results point to a critical role of the PRG3 and PRG5 C-termini in shaping early neuronal morphology. However, the results suggest that the C-terminus alone might not be sufficient for promoting the morphological effects induced by PRG3 and PRG5.

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Signal transduction mechanisms in the regulation of phospholipases

Patil,

Bhatia,

Samant

et al. 2023

Phospholipases in Physiology and Pathology

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Plasma membrane phospholipid phosphatase-related proteins as pleiotropic regulators of neuron growth and excitability

Abstract: Plasma membrane phospholipid phosphatase-related proteins as pleiotropic regulators of neuron growth and excitability.

Cited by 7 publications

References 154 publications

Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

Phosphorylation of PLPPR3 membrane proteins as signaling integrator at neuronal synapses

PRG3 and PRG5 C-Termini: Important Players in Early Neuronal Differentiation

Signal transduction mechanisms in the regulation of phospholipases

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