The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase

Tsuboi, Nobuyuki; Utsunomiya, Tohru; Roberts, Richard L.; Itô, Hideyuki; Takahashi, Keiko; Noda, Masaharu; Takahashi, Takamune

doi:10.1042/bj20071317

Cited by 45 publications

(56 citation statements)

References 35 publications

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“…9 These growth inhibitory functions of DEP-1 are consistent with the nature of some of its reported substrates, which include the PDGF-␤, HGF (Met), and VEGF (VEGFR2) receptors as well as Src family kinases (SFKs), ERK1/2, and the p85 subunit of PI3K. [10][11][12][13][14][15][16][17][18] DEP-1 also dephosphorylates proteins from the cell-cell junctional complexes including p120catenin, occludin, and ZO-1, which might impact biologic functions dependent on the loosening/strengthening of intercellular contacts. 11,14,19 VEGFR2 is a potent activator of the angiogenic response and is the main mediator of the mitogenic, chemotactic, permeability, and survival effects of VEGF in normal and tumor-associated vessels.…”

Section: Introductionmentioning

confidence: 49%

Tyrosine phosphorylation of DEP-1/CD148 as a mechanism controlling Src kinase activation, endothelial cell permeability, invasion, and capillary formation

Spring

Chabot

Langlois

et al. 2012

Blood

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DEP-1/CD148 is a receptor-like protein tyrosine phosphatase with antiproliferative and tumor-suppressive functions. Interestingly, it also positively regulates Src family kinases in hematopoietic and endothelial cells, where we showed it promotes VE-cadherin-associated Src activation and endothelial cell survival upon VEGF stimulation. However, the molecular mechanism involved and its biologic functions in endothelial cells remain illdefined. We demonstrate here that DEP-1 is phosphorylated in a Src-and Fyndependent manner on Y1311 and Y1320, IntroductionDEP-1/CD148 (also called PTP or PTPRJ) is a receptor-like protein tyrosine phosphatase (PTP) expressed in several cell types including epithelial, endothelial, and hematopoietic cells. 1 It encompasses an extracellular domain containing 8 fibronectin-type IIIlike motifs, a transmembrane domain, a single intracellular catalytic domain, and a short C-terminal tail. 2 Initial studies demonstrated that its expression increases with cell density and suggested a function in cell contact-mediated growth inhibition. 2,3 Overexpression of DEP-1 in cancer cells was also reported to inhibit their growth, while thyroid cell transformation was associated with its decreased expression, indicative of a role for DEP-1 as a tumor suppressor. 4-8 DEP-1 was further identified as the gene associated with the mouse colon cancer susceptibility locus (Scc1), and was found to be frequently deleted and mutated in human cancers. 9 These growth inhibitory functions of DEP-1 are consistent with the nature of some of its reported substrates, which include the PDGF-␤, HGF (Met), and VEGF (VEGFR2) receptors as well as Src family kinases (SFKs), ERK1/2, and the p85 subunit of PI3K. 10-18 DEP-1 also dephosphorylates proteins from the cell-cell junctional complexes including p120catenin, occludin, and ZO-1, which might impact biologic functions dependent on the loosening/strengthening of intercellular contacts. 11,14,19 VEGFR2 is a potent activator of the angiogenic response and is the main mediator of the mitogenic, chemotactic, permeability, and survival effects of VEGF in normal and tumor-associated vessels. 20 VE-cadherin adhesion complexes are important sites of VEGFdependent signaling in confluent cells, as activated VEGFR2 associates to these complexes to mediate Akt activation and cell survival. 21 DEP-1 was shown to colocalize to these sites and to attenuate the phosphorylation of VEGFR2, resulting in the impaired activation of ERK1/2 and the contact inhibition of endothelial cell proliferation. 13,22 However, DEP-1 was also reported to positively regulate VE-cadherin-associated Src and Akt and to promote VEGF-dependent endothelial cell survival. 15 Consistent with these distinct in vitro functions, inactivation of DEP-1 in mice via the swapping of its catalytic domain and C-terminal tail with GFP revealed both positive and negative regulatory effects in vascular development, and resulted in defective vessel remodeling and branching in addition to increased endothelial cell proliferati...

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Section: Introductionmentioning

confidence: 49%

Tyrosine phosphorylation of DEP-1/CD148 as a mechanism controlling Src kinase activation, endothelial cell permeability, invasion, and capillary formation

Spring

Chabot

Langlois

et al. 2012

Blood

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“…Last, loss of heterozygosity at the protein tyrosine phosphatase, receptor type J (CD148) locus is observed frequently in human cancers, implicating CD148 as a tumor suppressor (13). Consistent with its strong growth-inhibitory activity, CD148 dephosphorylates and suppresses growth factor receptors and their signaling proteins, including VEGF receptor 2 (VEGFR2) (14,15), EGF receptor (EGFR) (16,17), hepatocyte growth factor receptor (HGFR) (7,18), FGF receptor (FGFR) (7), PGDF receptor (PDGFR) (19), Erk1/2 (17,20), phospholipase Cγ1 (21), and p85 (22). Thus, CD148 is thought to function as a suppressor of growth factor signals and to inhibit cell growth and transformation.…”

mentioning

confidence: 99%

Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase

Takahashi¹,

Mernaugh²,

Friedman³

et al. 2012

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

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108

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CD148 is a receptor-type protein tyrosine phosphatase that is expressed in several cell types, including vascular endothelial cells and duct epithelial cells. Growing evidence demonstrates a prominent role for CD148 in negative regulation of growth factor signals, suppressing cell proliferation and transformation. However, its extracellular ligand(s) remain unknown. To identify the ligand(s) of CD148, we introduced HA-tagged CD148 into cultured endothelial cells and then isolated its interacting extracellular protein(s) by biotin surface labeling and subsequent affinity purifications. The binding proteins were identified by mass spectrometry. Here we report that soluble thrombospondin-1 (TSP1) binds to the extracellular part of CD148 with high affinity and specificity, and its binding increases CD148 catalytic activity, leading to dephosphorylation of the substrate proteins. Consistent with these findings, introduction of CD148 conferred TSP1-mediated inhibition of cell growth to cells which lack CD148 and TSP1 inhibition of growth. Further, we demonstrate that TSP1-mediated inhibition of endothelial cell growth is antagonized by soluble CD148 ectodomain as well as by CD148 gene silencing. These findings provide evidence that CD148 functions as a receptor for TSP1 and mediates its inhibition of cell growth.growth factor signaling | EGF receptor | VEGF receptor | ERK

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“…These include PDGFR, p120 catenin (CTND1), hepatocyte growth factor receptor, SRC kinase, VEGFR2, phosphatidylinositol 3-kinase regulatory subunit ␣ (P85A), and RET receptor kinase (5,(11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Tumor Suppressor Density-enhanced Phosphatase-1 (DEP-1) Inhibits the RAS Pathway by Direct Dephosphorylation of ERK1/2 Kinases

Sacco

Tinti

Palma

et al. 2009

Journal of Biological Chemistry

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Density-enhanced phosphatase-1 (DEP-1) is a trans-membrane receptor protein-tyrosine phosphatase that plays a recognized prominent role as a tumor suppressor. However, the mechanistic details underlying its function are poorly understood because its primary physiological substrate(s) have not been firmly established. To shed light on the mechanisms underlying the anti-proliferative role of this phosphatase, we set out to identify new DEP-1 substrates by a novel approach based on screening of high density peptide arrays. The results of the array experiment were combined with a bioinformatics filter to identify eight potential DEP-1 targets among the proteins annotated in the MAPK pathway. In this study we show that one of these potential targets, the ERK1/2, is indeed a direct DEP-1 substrate in vivo. Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. After epidermal growth factor stimulation, the phosphorylation of the activation loop of ERK1/2 can be modulated by changing the concentration of DEP-1, without affecting the activity of the upstream kinase MEK. In addition, we show that DEP-1 contains a KIM-like motif to recruit ERK1/2 proteins by a docking mechanism mediated by the common docking domain in ERK1/2. ERK proteins that are mutated in the conserved docking domain become insensitive to DEP-1 de-phosphorylation. Overall this study provides novel insights into the anti-proliferative role of this phosphatase and proposes a new mechanism that may also be relevant for the regulation of density-dependent growth inhibition. DEP-14 (also known as CD148, HPTP, and PTPRJ) is a class III receptor protein-tyrosine phosphatase, characterized by eight fibronectin type III repeats within the extracellular domain, a trans-membrane region, and a single cytosolic catalytic domain (1, 2). DEP-1 is expressed in all human hematopoietic cell lineages and was shown to negatively regulate T cell activation. In addition, several epithelial cell types display DEP-1 on their cell membranes (3). Homozygous DEP-1 mutant mice die before embryonic day 11.5, displaying severe defects in vascular organization (4). Interestingly, DEP-1 expression levels were found to augment with increased cell density (2), suggesting a role for this tyrosine phosphatase in sensing cell-cell contacts and in density-dependent growth inhibition (5). Moreover, accumulating evidence supports a prominent role for DEP-1 as a tumor suppressor as it negatively regulates cell proliferation and is poorly expressed in many cancer cell lines (6 -10). The observed anti-proliferative effect may be accounted for by the ability of DEP-1 to down-regulate growth factor signaling through the dephosphorylation of various receptor tyrosine kinases, such as PDGFR, VEGFR2, and MET (11-13), resulting in quenching of the downstream RAS-MAPK pathway. However, given the complex pleiotropic functions of DEP-1, it is also possible that additional regulatory ...

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The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase

Cited by 45 publications

References 35 publications

Tyrosine phosphorylation of DEP-1/CD148 as a mechanism controlling Src kinase activation, endothelial cell permeability, invasion, and capillary formation

Tyrosine phosphorylation of DEP-1/CD148 as a mechanism controlling Src kinase activation, endothelial cell permeability, invasion, and capillary formation

Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase

Tumor Suppressor Density-enhanced Phosphatase-1 (DEP-1) Inhibits the RAS Pathway by Direct Dephosphorylation of ERK1/2 Kinases

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