scholarly journals Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function

2011 ◽  
Vol 286 (18) ◽  
pp. 15980-15988 ◽  
Author(s):  
Yiru Xu ◽  
Wei Xia ◽  
Dustin Baker ◽  
Jin Zhou ◽  
Hyuk Chol Cha ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
Human Keratinocytes ◽  
Primary Human Keratinocytes ◽  
Protein Tyrosine ◽  
Hepatocyte Growth

Protein tyrosine phosphorylation is a ubiquitous, fundamental biochemical mechanism that regulates essential eukaryotic cellular functions. The level of tyrosine phosphorylation of specific proteins is finely tuned by the dynamic balance between protein tyrosine kinase and protein tyrosine phosphatase activities. Hepatocyte growth factor receptor (also known as Met), a receptor protein tyrosine kinase, is a major regulator of proliferation, migration, and survival for many epithelial cell types. We report here that receptor-type protein tyrosine phosphatase β (RPTP-β) specifically dephosphorylates Met and thereby regulates its function. Expression of RPTP-β, but not other RPTP family members or catalytically inactive forms of RPTP-β, reduces hepatocyte growth factor (HGF)-stimulated Met tyrosine phosphorylation in HEK293 cells. Expression of RPTP-β in primary human keratinocytes reduces both basal and HGF-induced Met phosphorylation at tyrosine 1356 and inhibits downstream MEK1/2 and Erk activation. Furthermore, shRNA-mediated knockdown of endogenous RPTP-β increases basal and HGF-stimulated Met phosphorylation at tyrosine 1356 in primary human keratinocytes. Purified RPTP-β intracellular domain preferentially dephosphorylates purified Met at tyrosine 1356 in vitro. In addition, the substrate-trapping mutant of RPTP-β specifically interacts with Met in intact cells. Expression of RPTP-β in human primary keratinocytes reduces HGF induction of VEGF expression, proliferation, and motility. Taken together, the above data indicate that RPTP-β is a key regulator of Met function.

scholarly journals Protein tyrosine phosphatase PTP-S binds to the juxtamembrane region of the hepatocyte growth factor receptor Met

1998 ◽  
Vol 336 (1) ◽  
pp. 235-239 ◽  
Author(s):  
Emma VILLA-MORUZZI ◽  
Franca PUNTONI ◽  
Alberto BARDELLI ◽  
Elisa VIGNA ◽  
Sabrina DE ROSA ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Extract ◽  
Affinity Column ◽  
Binding Region ◽  
Protein Tyrosine ◽  
Juxtamembrane Region ◽  
Hepatocyte Growth

We reported previously that a protein tyrosine phosphatase (PTP) activity is associated with the immunoprecipitated hepatocyte growth factor (HGF) receptor, also known as Met. The activity increased reversibly when Met was stimulated by HGF and decreased when Met was inactivated by PMA. To identify the PTP-binding region, we used deletion mutants of the receptor β-subunit. The PTP activity did not associate with Tpr–Met, a construct containing residues 1010–1390 of Met fused to Tpr. In contrast, PTP activity was present when the expressed protein contained the full juxtamembrane region (residues 956–1390 of Met) or part of this region (residues 957–1390 or 995–1390), indicating that the PTP-binding region is between residues 995 and 1009. This region includes Tyr1003, a site involved in Met downstream signalling. Incubation of Met immunoprecipitated from GTL-16 cells with an 8-mer phosphopeptide derived from residues 1003–1010 induced a marked decrease in the associated PTP activity, suggesting that the peptide reproduced the PTP-binding region. Mutation of Glu, Asp or Arg at positions -4, -1 or +1 respectively relative to Tyr1003 in a 9-mer peptide (residues 999–1007) abolished the ability of the peptide to decrease the PTP activity associated with Met. Phosphorylation of Tyr1003 was not required for PTP binding, since: (1) both phospho- and dephospho-peptides on a solid bead bound PTP activity from a GTL-16 cell extract, and (2) PTP activity was associated with a Met deletion mutant lacking residues 1–955 in which Tyr1003 had been changed into Phe. In order to partially purify the PTP from the GTL-16 cell extract, an affinity column was prepared using the Met-derived peptide comprising residues 998–1007. Less than 0.1% of the total cellular PTP was retained by the column, and was eluted with low salt concentrations. Using antibodies, this PTP was identified as PTP-S, a soluble PTP present in epithelial cells and fibroblasts.

scholarly journals A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signalling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Minseong Kim ◽  
Carmen Reinhard ◽  
Christof Niehrs
Keyword(s):  
Ubiquitin Ligase ◽  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
Ring Finger ◽  
Wnt Signalling ◽  
Protein Tyrosine ◽  
Mesenchymal Epithelial Transition Factor ◽  
Hepatocyte Growth ◽  
Mesenchymal Epithelial Transition

Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that targets Wnt receptors for ubiquitination and lysosomal degradation. Previously we showed that dephosphorylation of an endocytic tyrosine motif (4Y motif) in ZNRF3 by protein tyrosine phosphatase receptor-type kappa (PTPRK) promotes ZNRF3 internalization and Wnt receptor degradation (Chang et al. 2020). However, a responsible protein tyrosine kinase(s) (PTK) phosphorylating the 4Y motif remained elusive. Here we identify the proto-oncogene MET (mesenchymal-epithelial transition factor) as a 4Y kinase. MET binds to ZNRF3 and induces 4Y phosphorylation, stimulated by the MET ligand HGF (hepatocyte growth factor, scatter factor). HGF-MET signalling reduces ZNRF3-dependent Wnt receptor degradation thereby enhancing Wnt/b-catenin signalling. Conversely, depletion or pharmacological inhibition of MET promotes internalization of ZNRF3 and Wnt receptor degradation. We conclude that HGF-MET signalling phosphorylates- and PTPRK dephosphorylates ZNRF3 to regulate ZNRF3 internalization, functioning as a rheostat for Wnt signalling that may offer novel opportunities for therapeutic intervention.

scholarly journals Regulation of the interaction of nicotinic acetylcholine receptors with the cytoskeleton by agrin-activated protein tyrosine kinase.

1995 ◽  
Vol 128 (6) ◽  
pp. 1121-1129 ◽  
Author(s):  
B G Wallace
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Nicotinic Acetylcholine Receptors ◽  
Protein Tyrosine Phosphatase ◽  
Acetylcholine Receptors ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
Beta Subunit ◽  
Nicotinic Acetylcholine ◽  
Protein Tyrosine

Agrin induces the accumulation of nicotinic acetylcholine receptors (AChRs) in the myofiber membrane at synaptic sites in vertebrate skeletal muscle and causes an increase in tyrosine phosphorylation of the AChR beta subunit. To examine further the mechanism of agrin-induced AChR phosphorylation and the relationship between changes in protein phosphorylation and AChR aggregation, the effect of the protein tyrosine phosphatase inhibitor sodium pervanadate was tested on chick myotubes in culture. Pervanadate caused an increase in the phosphotyrosine content of a variety of proteins, including the AChR. Pervanadate also prevented agrin-induced AChR aggregation and slowed the rate at which AChRs were extracted from intact myotubes by mild detergent treatment. The rate at which phosphorylation of the AChR beta subunit and receptor detergent extractability changed following pervanadate-induced phosphatase inhibition was increased by agrin, indicating that agrin activates a protein tyrosine kinase rather than inhibiting a protein tyrosine phosphatase. The present results, taken together with previous findings on the inhibition of agrin-induced AChR aggregation by protein kinase inhibitors, demonstrate that protein tyrosine phosphorylation regulates the formation and stability of AChR aggregates, apparently by strengthening the interaction between AChRs and the cytoskelton.

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