Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 721-732 ◽  
Author(s):  
Sabine H. Wimmer-Kleikamp ◽  
Eva Nievergall ◽  
Kristina Gegenbauer ◽  
Samantha Adikari ◽  
Mariam Mansour ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Cell Movement ◽  
Leukemia Cells ◽  
Cell Contact ◽  
Eph Receptors ◽  
Protein Tyrosine ◽  
Phosphotyrosine Signaling ◽  
Cell Cell

Abstract Signaling by Eph receptors and cell-surface ephrin ligands modulates adhesive cell properties and thereby coordinates cell movement and positioning in normal and oncogenic development. While cell contact–dependent Eph activation frequently leads to cell-cell repulsion, also the diametrically opposite response, cell-cell adhesion, is a probable outcome. However, the molecular principles regulating such disparate functions have remained controversial. We have examined cell-biologic mechanisms underlying this switch by analyzing ephrin-A5–induced cell-morphologic changes of EphA3-positive LK63 pre-B acute lymphoblastic leukemia cells. Their exposure to ephrin-A5 surfaces leads to a rapid conversion from a suspended/nonpolarized to an adherent/polarized cell type, a transition that relies on EphA3 functions operating in the absence of Eph-kinase signaling. Cell morphology change and adhesion of LK63 cells are effectively attenuated by endogenous protein tyrosine phosphatase (PTP) activity, whereby PTP inhibition and productive EphA3-phosphotyrosine signaling reverse the phenotype to nonadherent cells with a condensed cytoskeleton. Our findings suggest that Eph-associated PTP activities not only control receptor phosphorylation levels, but as a result switch the response to ephrin contact from repulsion to adhesion, which may play a role in the pathology of hematopoietic tumors.

scholarly journals Cell surface expression of receptor protein tyrosine phosphatase RPTP mu is regulated by cell-cell contact.

1995 ◽  
Vol 131 (1) ◽  
pp. 251-260 ◽  
Author(s):  
M F Gebbink ◽  
G C Zondag ◽  
G M Koningstein ◽  
E Feiken ◽  
R W Wubbolts ◽  
...  
Keyword(s):  
Cell Surface ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Surface Expression ◽  
Lung Epithelial Cells ◽  
Receptor Protein ◽  
Cell Surface Expression ◽  
Cell Contact ◽  
Protein Tyrosine ◽  
Cell Cell

RPTP mu is a transmembrane protein tyrosine phosphatase with an adhesion molecule-like ectodomain. It has recently been shown that RPTP mu mediates homophilic interactions when expressed in insect cells. In this study, we have examined how RPTP mu may function as a cell contact receptor in mink lung epithelial cells, which express RPTPmu endogenously, as well as in transfected 3T3 cells. We find that RPTP mu has a relatively short half-life (3-4 hours) and undergoes posttranslational cleavage into two noncovalently associated subunits, with both cleaved and uncleaved molecules being present on the cell surface (roughly at a 1:1 ratio); shedding of the ectodomain subunit is observed in exponentially growing cells. Immunofluorescence analysis reveals that surface expression of RPTPmu is restricted to regions of tight cell-cell contact. RPTPmu surface expression increases significantly with increasing cell density. This density-induced upregulation of RPTP mu is independent of its catalytic activity and is also observed when transcription is driven by a constitutive promoter, indicating that modulation of RPTPmu surface expression occurs posttranscriptionally. Based on our results, we propose the following model of RPTP mu function: In the absence of cell-cell contact, newly synthesized RPTP mu molecules are rapidly cleared from the cell surface. Cell-cell contact causes RPTPmu to be trapped at the surface through homophilic binding, resulting in accumulation of RPTP mu at intercellular contact regions. This contact-induced clustering of RPTPmu may then lead to tyrosine dephosphorylation of intracellular substrates at cell-cell contacts.

scholarly journals Regulation of Signaling at Regions of Cell-Cell Contact by Endoplasmic Reticulum-Bound Protein-Tyrosine Phosphatase 1B

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e36633 ◽  
Author(s):  
Fawaz G. Haj ◽  
Ola Sabet ◽  
Ali Kinkhabwala ◽  
Sabine Wimmer-Kleikamp ◽  
Vassilis Roukos ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Contact ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Cell Cell

scholarly journals Homophilic binding of PTP mu, a receptor-type protein tyrosine phosphatase, can mediate cell-cell aggregation

1993 ◽  
Vol 122 (4) ◽  
pp. 961-972 ◽  
Author(s):  
SM Brady-Kalnay ◽  
AJ Flint ◽  
NK Tonks
Keyword(s):  
Fusion Protein ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Recombinant Baculovirus ◽  
Sf9 Cells ◽  
Homophilic Binding ◽  
Protein Tyrosine ◽  
Baculovirus Infection ◽  
Induced Aggregation ◽  
Cell Cell

The receptor-like protein tyrosine phosphatase, PTPmu, displays structural similarity to cell-cell adhesion molecules of the immunoglobulin superfamily. We have investigated the ability of human PTPmu to function in such a capacity. Expression of PTPmu, with or without the PTPase domains, by recombinant baculovirus infection of Sf9 cells induced their aggregation. However, neither a chimeric form of PTPmu, containing the extracellular and transmembrane segments of the EGF receptor and the intracellular segment of PTPmu, nor the intracellular segment of PTPmu expressed as a soluble protein induced aggregation. PTPmu mediates aggregation via a homophilic mechanism, as judged by lack of incorporation of uninfected Sf9 cells into aggregates of PTPmu-expressing cells. Homophilic binding has been demonstrated between PTPmu-coated fluorescent beads (Covaspheres) and endogenously expressed PTPmu on MvLu cells. Additionally the PTPmu-coated beads specifically bound to a bacterially expressed glutathione-S-transferase fusion protein containing the extracellular segment of PTPmu (GST/PTPmu) adsorbed to petri dishes. Covaspheres coated with the GST/PTPmu fusion protein aggregated in vitro and also bound to PTPmu expressed endogenously on MvLu cells. These results suggest that the ligand for this transmembrane PTPase is another PTPmu molecule on an adjacent cell. Thus homophilic binding interactions may be an important component of the function of PTPmu in vivo.

scholarly journals The Role of Protein Tyrosine Phosphatase PTP4A3 in T-Cell Acute Lymphoblastic Leukemia Progression

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2539-2539
Author(s):  
Min Wei ◽  
Jessica Blackburn
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Phosphatase ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Causative Role ◽  
Protein Tyrosine ◽  
Cell Acute Lymphoblastic Leukemia

The tyrosine protein tyrosine phosphatase PTP4A3 has been extensively reported to play a causative role in numerous cancers, including several types of acute leukemia. We found PTP4A3 to be highly expressed in T-cell Acute Lymphoblastic Leukemia samples, and show that PTP4A3 accelerates T-ALL onset and increases the invasive ability of T-ALL cells in a zebrafish model, and is required for T-ALL engraftment and progression in mouse xenograft. Our in vitro studies showed that PTP43A3 enhances T-ALL migration, in part via modulation of SRC signaling. However, whether SRC is a direct substrate of PTP4A3, and whether the phosphatase activity of PTP4A3 actually plays a role in T-ALL or other types of leukemia progression is unknown and remains a major question in the field. We used a BioID-based proximity labeling approach combined with PTP4A3 substrate trapping mutant pull down assay to capture the PTP4A3 substrates candidates. BioID, a biotin ligase, was fused to PTP4A3 to generate a Biotin-PTP4A3 (BP) fusion protein. The overexpression of BP in T-ALL cell lines led to biotin modification of 288 PTP4A3 proximal proteins, including the potential direct PTP4A3 substrates. PANTHER pathway analysis showed that PTP4A3 interacting proteins are largely clustered in the T-cell activation, PDGF signaling, and angiogenesis. We are in process of validating potential substrates using immunoprecipitation and phosphoenrichement assays. Finally, we are using a novel zebrafish Myc+PTP4A3 induced T-ALL model to assess the function of PTP4A3 in leukemia progression. We have created several PTP4A3 protein mutants, including a phosphatase-dead mutant, a mutant unable to bind magnesium transporter, and a prenylation deficient mutant, and are in process of assessing the effects of these mutants in T-ALL onset and progression in our in vivo model. In total, these studies will allow us to better understand function of PTP4A3 in T-ALL progression, and may provide a strong rationale for the development of PTP4A3 inhibitors for use in leukemia. Disclosures No relevant conflicts of interest to declare.

RPTPμ and protein tyrosine phosphorylation regulate K+channel mRNA expression in adult cardiac myocytes

2000 ◽  
Vol 278 (2) ◽  
pp. C397-C403 ◽  
Author(s):  
Kenneth M. Hershman ◽  
Edwin S. Levitan
Keyword(s):  
Mrna Expression ◽  
Tyrosine Phosphorylation ◽  
Cardiac Myocytes ◽  
Protein Tyrosine Phosphatase ◽  
Cardiac Myocyte ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Protein Tyrosine ◽  
Cell Cell

Previously, we reported that cell-cell contact regulates K+channel mRNA expression in cultured adult rat cardiac myocytes. Here we show that exposing cardiac myocytes to tyrosine kinase inhibitors (genistein, tyrphostin A25), but not inactive analogs, prevents downregulation of Kv1.5 mRNA and upregulation of Kv4.2 mRNA normally observed when they are cultured under low-density conditions. Furthermore, cardiac myocytes cocultured with cells that endogenously (Mv 1 Lu) or heterologously (Chinese hamster ovary cells) express the receptor-type protein tyrosine phosphatase μ (RPTPμ) display Kv1.5 mRNA levels paralleling that which was observed in myocytes cultured under high-density conditions and in intact tissue. In contrast, myocytes cocultured with control cells failed to produce this response. Finally, it is shown that Kv4.2 mRNA expression is unaffected by RPTPμ. These findings reveal that multiple tyrosine phosphorylation-dependent mechanisms control cardiac myocyte K+channel genes. Furthermore, we conclude that RPTPμ specifically regulates cardiac myocyte Kv1.5 mRNA expression. Thus this receptor protein tyrosine phosphatase may be important in responses to pathological conditions associated with the loss of cell-cell interactions in the heart.

scholarly journals The PTPμ Protein-tyrosine Phosphatase Binds and Recruits the Scaffolding Protein RACK1 to Cell-Cell Contacts

2001 ◽  
Vol 276 (18) ◽  
pp. 14896-14901 ◽  
Author(s):  
Tracy Mourton ◽  
Carina B. Hellberg ◽  
Susan M. Burden-Gulley ◽  
Jason Hinman ◽  
Amy Rhee ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Scaffolding Protein ◽  
Cell Contacts ◽  
Protein Tyrosine ◽  
Cell Cell
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