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.

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

2016 ◽  
Vol 473 (2) ◽  
pp. e5-e8 ◽  
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.

scholarly journals Regulatory Functions of Protein Tyrosine Phosphatase Receptor Type O in Immune Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Feiling Xie ◽  
Hongmei Dong ◽  
Hao Zhang
Keyword(s):  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Protein Tyrosine Phosphatase ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Receptor Type ◽  
Protein Tyrosine ◽  
Cellular Processes

The members of the protein tyrosine phosphatase (PTP) family are key regulators in multiple signal transduction pathways and therefore they play important roles in many cellular processes, including immune response. As a member of PTP family, protein tyrosine phosphatase receptor type O (PTPRO) belongs to the R3 receptor-like protein tyrosine phosphatases. The expression of PTPRO isoforms is tissue-specific and the truncated PTPRO (PTPROt) is mainly observed in hematopoietic cells, including B cells, T cells, macrophages and other immune cells. Therefore, PTPROt may play an important role in immune cells by affecting their growth, differentiation, activation and immune responses. In this review, we will focus on the regulatory roles and underlying molecular mechanisms of PTPRO/PTPROt in immune cells, including B cells, T cells, and macrophages.

Structure, modelling, and molecular dynamics studies of the inhibition of protein tyrosine phosphatase 1B by sulfotyrosine peptides

1999 ◽  
Vol 77 (5) ◽  
pp. 469-486 ◽  
Author(s):  
Nicholas R Glover ◽  
Alan S Tracey
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modelling ◽  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Nuclear Overhauser Effect ◽  
Tyrosine Phosphatase ◽  
Nmr Studies ◽  
Protein Tyrosine ◽  
Cellular Processes ◽  
Active Site Pocket

The protein tyrosine phosphatases comprise a class of enzymes that are crucial for the regulation of a number of cellular processes. Because of this, they are attracting increasing attention, not only as legitimate therapeutic targets, but also because of their relationship to many fundamental cellular processes. Certain sulfotyrosine peptides derived from casein are known to be good inhibitors of the protein tyrosine phosphatase, PTP1B. In this study, NMR transfer nuclear Overhauser effect studies have been used to ascertain the bound-state conformation adopted by the 12-amino acid residue casein-derived peptide, CAS200 (NANEEE(sY)SIGSA) and N-terminal truncated forms of this peptide, CAS203 and CAS205. Each of the peptides were found to bind in an extended beta-strand conformation. Extensive molecular modelling and molecular dynamics simulations of the PTP1B/peptide complexes, in a fully hydrated model, allowed a detailed description of the potential sources of the binding interactions to be developed. In agreement with the NMR studies, the modelling provided a picture of binding of CAS200 in which only the central (E203- I208) residues contributed significantly to the binding while the 3 N-terminal and 3 C-terminal residues were quite fluxional. Critical cationic surface residues, lying near to, but outside the active site pocket were the source of strong stabilizing forces that complemented the stabilizing interactions of the active site pocket. Electrostatic, hydrophobic, and hydrogen bonding interactions, in a residue specific manner, were all found to make significant contributions to the binding of these inhibitors.Key words: protein tyrosine phosphatase, PTP1B, casein peptide, inhibitor, NMR structure, molecular modelling, molecular dynamics.

scholarly journals Syndecan-2 is a novel ligand for the protein tyrosine phosphatase receptor CD148

2011 ◽  
Vol 22 (19) ◽  
pp. 3609-3624 ◽  
Author(s):  
James R. Whiteford ◽  
Xiaojie Xian ◽  
Claire Chaussade ◽  
Bart Vanhaesebroeck ◽  
Sussan Nourshargh ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Protein Tyrosine Phosphatase ◽  
Transmembrane Domain ◽  
Core Protein ◽  
Tyrosine Phosphatase ◽  
Β1 Integrin ◽  
Potential Implication ◽  
Protein Tyrosine ◽  
Cellular Processes ◽  
A Cell

Syndecan-2 is a heparan sulfate proteoglycan that has a cell adhesion regulatory domain contained within its extracellular core protein. Cell adhesion to the syndecan-2 extracellular domain (S2ED) is β1 integrin dependent; however, syndecan-2 is not an integrin ligand. Here the protein tyrosine phosphatase receptor CD148 is shown to be a key intermediary in cell adhesion to S2ED, with downstream β1 integrin–mediated adhesion and cytoskeletal organization. We show that S2ED is a novel ligand for CD148 and identify the region proximal to the transmembrane domain of syndecan-2 as the site of interaction with CD148. A mechanism for the transduction of the signal from CD148 to β1 integrins is elucidated requiring Src kinase and potential implication of the C2β isoform of phosphatidylinositol 3 kinase. Our data uncover a novel pathway for β1 integrin–mediated adhesion of importance in cellular processes such as angiogenesis and inflammation.

scholarly journals Overexpression of the Protein Tyrosine Phosphatase PRL-2 Correlates with Breast Tumor Formation and Progression

2010 ◽  
Vol 70 (21) ◽  
pp. 8959-8967 ◽  
Author(s):  
Serge Hardy ◽  
Nau Nau Wong ◽  
William J. Muller ◽  
Morag Park ◽  
Michel L. Tremblay
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Breast Tumor ◽  
Tyrosine Phosphatase ◽  
Tumor Formation ◽  
Protein Tyrosine

scholarly journals Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

2015 ◽  
Vol 35 (8) ◽  
pp. 1401-1413 ◽  
Author(s):  
Hye Shin Lee ◽  
Mujeeburahiman Cheerathodi ◽  
Sankar P. Chaki ◽  
Steve B. Reyes ◽  
Yanhua Zheng ◽  
...  
Keyword(s):  
Cell Motility ◽  
Protein Tyrosine Phosphatase ◽  
Protein Complexes ◽  
Tyrosine Phosphatase ◽  
Leading Edge ◽  
Protein Tyrosine ◽  
Motile Cells ◽  
Signaling Events ◽  
Gdp Dissociation Inhibitor ◽  
Migrating Cells

Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor β8 integrin that plays essential roles in directional cell motility. β8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells.

The ESCRT machinery: a cellular apparatus for sorting and scission

2010 ◽  
Vol 38 (6) ◽  
pp. 1397-1412 ◽  
Author(s):  
Jeremy Carlton
Keyword(s):  
Protein Complexes ◽  
Multivesicular Bodies ◽  
Particle Assembly ◽  
Endosomal Sorting ◽  
Cellular Processes ◽  
Daughter Cells ◽  
Escrt Machinery ◽  
Membrane Fission

The ESCRT (endosomal sorting complex required for transport) machinery is a group of multisubunit protein complexes conserved across phyla that are involved in a range of diverse cellular processes. ESCRT proteins regulate the biogenesis of MVBs (multivesicular bodies) and the sorting of ubiquitinated cargos on to ILVs (intraluminal vesicles) within these MVBs. These proteins are also recruited to sites of retroviral particle assembly, where they provide an activity that allows release of these retroviruses. More recently, these proteins have been shown to be recruited to the intracellular bridge linking daughter cells at the end of mitosis, where they act to ensure the separation of these cells through the process of cytokinesis. Although these cellular processes are diverse, they share a requirement for a topologically unique membrane-fission step for their completion. Current models suggest that the ESCRT machinery catalyses this membrane fission.

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.

E3 ubiquitin ligases

2005 ◽  
Vol 41 ◽  
pp. 15-30 ◽  
Author(s):  
Helen C. Ardley ◽  
Philip A. Robinson
Keyword(s):  
Protein Complexes ◽  
Loss Of Function ◽  
Direct Role ◽  
Cellular Processes ◽  
Substrate Protein ◽  
Protein Ubiquitination ◽  
C Terminus ◽  
Full Complement ◽  
Spatio Temporal ◽  
Eukaryotic Organisms

The selectivity of the ubiquitin–26 S proteasome system (UPS) for a particular substrate protein relies on the interaction between a ubiquitin-conjugating enzyme (E2, of which a cell contains relatively few) and a ubiquitin–protein ligase (E3, of which there are possibly hundreds). Post-translational modifications of the protein substrate, such as phosphorylation or hydroxylation, are often required prior to its selection. In this way, the precise spatio-temporal targeting and degradation of a given substrate can be achieved. The E3s are a large, diverse group of proteins, characterized by one of several defining motifs. These include a HECT (homologous to E6-associated protein C-terminus), RING (really interesting new gene) or U-box (a modified RING motif without the full complement of Zn2+-binding ligands) domain. Whereas HECT E3s have a direct role in catalysis during ubiquitination, RING and U-box E3s facilitate protein ubiquitination. These latter two E3 types act as adaptor-like molecules. They bring an E2 and a substrate into sufficiently close proximity to promote the substrate's ubiquitination. Although many RING-type E3s, such as MDM2 (murine double minute clone 2 oncoprotein) and c-Cbl, can apparently act alone, others are found as components of much larger multi-protein complexes, such as the anaphase-promoting complex. Taken together, these multifaceted properties and interactions enable E3s to provide a powerful, and specific, mechanism for protein clearance within all cells of eukaryotic organisms. The importance of E3s is highlighted by the number of normal cellular processes they regulate, and the number of diseases associated with their loss of function or inappropriate targeting.

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