scholarly journals Axonal Regeneration by Glycosaminoglycan

2021 ◽  
Vol 9 ◽  
Author(s):  
Kazuma Sakamoto ◽  
Tomoya Ozaki ◽  
Kenji Kadomatsu
Keyword(s):  
Heparan Sulfate ◽  
Chondroitin Sulfate ◽  
Membrane Trafficking ◽  
Intracellular Signaling ◽  
Axonal Regeneration ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Tissue Elasticity ◽  
Surface Receptors ◽  
Cellular Processes

Like other biomolecules including nucleic acid and protein, glycan plays pivotal roles in various cellular processes. For instance, it modulates protein folding and stability, organizes extracellular matrix and tissue elasticity, and regulates membrane trafficking. In addition, cell-surface glycans are often utilized as entry receptors for viruses, including SARS-CoV-2. Nevertheless, its roles as ligands to specific surface receptors have not been well understood with a few exceptions such as selectins and siglecs. Recent reports have demonstrated that chondroitin sulfate and heparan sulfate, both of which are glycosaminoglycans, work as physiological ligands on their shared receptor, protein tyrosine phosphatase sigma (PTPσ). These two glycans differentially determine the fates of neuronal axons after injury in our central nervous system. That is, heparan sulfate promotes axonal regeneration while chondroitin sulfate inhibits it, inducing dystrophic endbulbs at the axon tips. In our recent study, we demonstrated that the chondroitin sulfate (CS)-PTPσ axis disrupted autophagy flux at the axon tips by dephosphorylating cortactin. In this minireview, we introduce how glycans work as physiological ligands and regulate their intracellular signaling, especially focusing on chondroitin sulfate.

scholarly journals Heparan Sulfate Proteoglycans Are Ligands for Receptor Protein Tyrosine Phosphatase σ

2002 ◽  
Vol 22 (6) ◽  
pp. 1881-1892 ◽  
Author(s):  
A. Radu Aricescu ◽  
Iain W. McKinnell ◽  
Willi Halfter ◽  
Andrew W. Stoker
Keyword(s):  
Heparan Sulfate ◽  
Basal Lamina ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Axon Growth ◽  
Growth Cones ◽  
Heparan Sulfate Proteoglycans ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatase

ABSTRACT RPTPσ is a cell adhesion molecule-like receptor protein tyrosine phosphatase involved in nervous system development. Its avian orthologue, known as cPTPσ or CRYPα, promotes intraretinal axon growth and controls the morphology of growth cones. The molecular mechanisms underlying the functions of cPTPσ are still to be determined, since neither its physiological ligand(s) nor its substrates have been described. Nevertheless, a major class of ligand(s) is present in the retinal basal lamina and glial endfeet, the potent native growth substrate for retinal axons. We demonstrate here that cPTPσ is a heparin-binding protein and that its basal lamina ligands include the heparan sulfate proteoglycans (HSPGs) agrin and collagen XVIII. These molecules interact with high affinity with cPTPσ in vitro, and this binding is totally dependent upon their heparan sulfate chains. Using molecular modelling and site-directed mutagenesis, a binding site for heparin and heparan sulfate was identified in the first immunoglobulin-like domain of cPTPσ. HSPGs are therefore a novel class of heterotypic ligand for cPTPσ, suggesting that cPTPσ signaling in axons and growth cones is directly responsive to matrix-associated cues.

scholarly journals Sulfation of Glycosaminoglycans Modulates the Cell Cycle of Embryonic Mouse Spinal Cord Neural Stem Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena Schaberg ◽  
Ursula Theocharidis ◽  
Marcus May ◽  
Katrin Lessmann ◽  
Timm Schroeder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Spinal Cord ◽  
Chondroitin Sulfate ◽  
Cell Cycle Progression ◽  
Cell Tracking ◽  
Tyrosine Phosphatase ◽  
Sodium Chlorate ◽  
Receptor Protein ◽  
Embryonic Mouse ◽  
Developing Spinal Cord

In the developing spinal cord neural stem and progenitor cells (NSPCs) secrete and are surrounded by extracellular matrix (ECM) molecules that influence their lineage decisions. The chondroitin sulfate proteoglycan (CSPG) DSD-1-PG is an isoform of receptor protein tyrosine phosphatase-beta/zeta (RPTPβ/ζ), a trans-membrane receptor expressed by NSPCs. The chondroitin sulfate glycosaminoglycan chains are sulfated at distinct positions by sulfotransferases, thereby generating the distinct DSD-1-epitope that is recognized by the monoclonal antibody (mAb) 473HD. We detected the epitope, the critical enzymes and RPTPβ/ζ in the developing spinal cord. To obtain insight into potential biological functions, we exposed spinal cord NSPCs to sodium chlorate. The reagent suppresses the sulfation of glycosaminoglycans, thereby erasing any sulfation code expressed by the glycosaminoglycan polymers. When NSPCs were treated with chlorate and cultivated in the presence of FGF2, their proliferation rate was clearly reduced, while NSPCs exposed to EGF were less affected. Time-lapse video microscopy and subsequent single-cell tracking revealed that pedigrees of NSPCs cultivated with FGF2 were strongly disrupted when sulfation was suppressed. Furthermore, the NSPCs displayed a protracted cell cycle length. We conclude that the inhibition of sulfation with sodium chlorate interferes with the FGF2-dependent cell cycle progression in spinal cord NSPCs.

scholarly journals Identification of sequences required for the efficient localization of the focal adhesion kinase, pp125FAK, to cellular focal adhesions.

1993 ◽  
Vol 123 (4) ◽  
pp. 993-1005 ◽  
Author(s):  
J D Hildebrand ◽  
M D Schaller ◽  
J T Parsons
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Intracellular Signaling ◽  
Protein Tyrosine Kinase ◽  
Focal Adhesions ◽  
Cellular Adhesion ◽  
Signaling Cascades ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Integrin Family

The integrin family of heterodimeric cell surface receptors play critical roles in multiple biological processes by mediating cellular adhesion to the extracellular matrix (ECM). Adhesion triggers intracellular signaling cascades, including tyrosine phosphorylation and elevation of [Ca2+]i. The Focal Adhesion Kinase (FAK or pp125FAK), a protein tyrosine kinase that colocalizes with integrins in cellular focal adhesions, is a prime candidate for a mediator of integrin signaling events. Here we report an analysis of the domain structure of FAK in which we have identified a contiguous stretch of 159 amino acids within the COOH terminus essential for correct subcellular localization. When placed in the context of an unrelated cytosolic protein, this Focal Adhesion Targeting (FAT) sequence functions to efficiently mediate the focal adhesion localization of this fusion protein. Furthermore, this analysis suggests that pp125FAK cannot be activated oncogenically by mutation. This result could be explained if pp125FK either exhibits a narrow substrate specificity or is diametrically opposed by cellular phosphatases or other cellular processes.

Structure and functions of His domain protein tyrosine phosphatase in receptor trafficking and cancer

2019 ◽  
Vol 97 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Guillaume Desrochers ◽  
Jalal M. Kazan ◽  
Arnim Pause
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Complexes ◽  
Tyrosine Phosphatase ◽  
Tumor Formation ◽  
Receptor Trafficking ◽  
Surface Receptors ◽  
Cellular Processes ◽  
Escrt Machinery ◽  
Modular Domain ◽  
Structure And Functions

Cell surface receptors trigger the activation of signaling pathways to regulate key cellular processes, including cell survival and proliferation. Internalization, sorting, and trafficking of activated receptors, therefore, play a major role in the regulation and attenuation of cell signaling. Efficient sorting of endocytosed receptors is performed by the ESCRT machinery, which targets receptors for degradation by the sequential establishment of protein complexes. These events are tightly regulated and malfunction of ESCRT components can lead to abnormal trafficking and sustained signaling and promote tumor formation or progression. In this review, we analyze the modular domain organization of the alternative ESCRT protein HD-PTP and its role in receptor trafficking and tumorigenesis.

scholarly journals Receptor-Like Protein Tyrosine Phosphatase α Homodimerizes on the Cell Surface

2000 ◽  
Vol 20 (16) ◽  
pp. 5917-5929 ◽  
Author(s):  
Guoqiang Jiang ◽  
Jeroen den Hertog ◽  
Tony Hunter
Keyword(s):  
Biological Activity ◽  
Cell Surface ◽  
Protein Tyrosine Phosphatase ◽  
Intracellular Signaling ◽  
Catalytic Domain ◽  
Transmembrane Domain ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Dependent Manner ◽  
Protein Tyrosine

ABSTRACT We reported previously that the N-terminal D1 catalytic domain of receptor protein-tyrosine phosphatase α (RPTPα) forms a symmetrical, inhibited dimer in a crystal structure, in which a helix-turn-helix wedge element from one monomer is inserted into the catalytic cleft of the other monomer. Previous functional studies also suggested that dimerization inhibits the biological activity of a CD45 chimeric RPTP and the catalytic activity of an isolated RPTPς D1 catalytic domain. Most recently, we have also shown that enforced dimerization inhibits the biological activity of full-length RPTPα in a wedge-dependent manner. The physiological significance of such inhibition is unknown, due to a lack of understanding of how RPTPα dimerization is regulated in vivo. In this study, we show that transiently expressed cell surface RPTPα exists predominantly as homodimers, suggesting that dimerization-mediated inhibition of RPTPα biological activity is likely to be physiologically relevant. Consistent with our published and unpublished crystallographic data, we show that mutations in the wedge region of D1 catalytic domain and deletion of the entire D2 catalytic domain independently reduced but did not abolish RPTPα homodimerization, suggesting that both domains are critically involved but that neither is essential for homodimerization. Finally, we also provide evidence that both the RPTPα extracellular domain and the transmembrane domain were independently able to homodimerize. These results lead us to propose a zipper model in which inactive RPTPα dimers are stabilized by multiple, relatively weak dimerization interfaces. Dimerization in this manner would provide a potential mechanism for negative regulation of RPTPα. Such RPTPα dimers could be activated by extracellular ligands or intracellular binding proteins that induce monomerization or by intracellular signaling events that induce an open conformation of the dimer.

scholarly journals Rabs in Signaling and Embryonic Development

2020 ◽  
Vol 21 (3) ◽  
pp. 1064 ◽  
Author(s):  
Sonya Nassari ◽  
Tomas Del Olmo ◽  
Steve Jean
Keyword(s):  
Embryonic Development ◽  
Membrane Trafficking ◽  
Intracellular Signaling ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Cellular Processes ◽  
Complex Process ◽  
Signaling Events ◽  
And Function

Rab GTPases play key roles in various cellular processes. They are essential, among other roles, to membrane trafficking and intracellular signaling events. Both trafficking and signaling events are crucial for proper embryonic development. Indeed, embryogenesis is a complex process in which cells respond to various signals and undergo dramatic changes in their shape, position, and function. Over the last few decades, cellular studies have highlighted the novel signaling roles played by Rab GTPases, while numerous studies have shed light on the important requirements of Rab proteins at various steps of embryonic development. In this review, we aimed to generate an overview of Rab contributions during animal embryogenesis. We first briefly summarize the involvement of Rabs in signaling events. We then extensively highlight the contribution of Rabs in shaping metazoan development and conclude with new approaches that will allow investigation of Rab functions in vivo.

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