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 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 receptor type C (PTPRC or CD45)

2021 ◽  
pp. jclinpath-2020-206927
Author(s):  
Maryam Ahmed Al Barashdi ◽  
Ahlam Ali ◽  
Mary Frances McMullin ◽  
Ken Mills
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Biological Activities ◽  
Tyrosine Phosphatase ◽  
Cell Types ◽  
Receptor Type ◽  
Future Research ◽  
Protein Tyrosine ◽  
Type C ◽  
Almost All

The leucocyte common antigen, protein tyrosine phosphatase receptor type C (PTPRC), also known as CD45, is a transmembrane glycoprotein, expressed on almost all haematopoietic cells except for mature erythrocytes, and is an essential regulator of T and B cell antigen receptor-mediated activation. Disruption of the equilibrium between protein tyrosine kinase and phosphatase activity (from CD45 and others) can result in immunodeficiency, autoimmunity, or malignancy. CD45 is normally present on the cell surface, therefore it works upstream of a large signalling network which differs between cell types, and thus the effects of CD45 on these cells are also different. However, it is becoming clear that CD45 plays an essential role in the innate immune system and this is likely to be a key area for future research. In this review of PTPRC (CD45), its structure and biological activities as well as abnormal expression of CD45 in leukaemia and lymphoma will be discussed.

Effects of protein tyrosine kinase and protein tyrosine phosphatase on apical K+ channels in the TAL

2001 ◽  
Vol 281 (4) ◽  
pp. C1188-C1195 ◽  
Author(s):  
Rui-Min Gu ◽  
Yuan Wei ◽  
John R. Falck ◽  
U. Murali Krishna ◽  
Wen-Hui Wang
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Patch Clamp Technique ◽  
K Channels ◽  
Protein Tyrosine ◽  
Herbimycin A

We have previously demonstrated that the protein level of c-Src, a nonreceptor type of protein tyrosine kinase (PTK), was higher in the renal medulla from rats on a K-deficient (KD) diet than that in rats on a high-K (HK) diet (Wang WH, Lerea KM, Chan M, and Giebisch G. Am J Physiol Renal Physiol 278: F165–F171, 2000). We have now used the patch-clamp technique to investigate the role of PTK in regulating the apical K channels in the medullary thick ascending limb (mTAL) of the rat kidney. Inhibition of PTK with herbimycin A increased NP o, a product of channel number ( N) and open probability ( P o), of the 70-pS K channel from 0.12 to 0.42 in the mTAL only from rats on a KD diet but had no significant effect in tubules from animals on a HK diet. In contrast, herbimycin A did not affect the activity of the 30-pS K channel in the mTAL from rats on a KD diet. Moreover, addition of N-methylsulfonyl-12,12-dibromododec-11-enamide, an agent that inhibits the cytochrome P-450-dependent production of 20-hydroxyeicosatetraenoic acid, further increased NP o of the 70-pS K channel in the presence of herbimycin A. Furthermore, Western blot detected the presence of PTP-1D, a membrane-associated protein tyrosine phosphatase (PTP), in the renal outer medulla. Inhibition of PTP with phenylarsine oxide (PAO) decreased NP o of the 70-pS K channel in the mTAL from rats on a HK diet. However, PAO did not inhibit the activity of the 30-pS K channel in the mTAL. The effect of PAO on the 70-pS K channel was due to indirectly stimulating PTK because pretreatment of the mTAL with herbimycin A abolished the inhibitory effect of PAO. Finally, addition of exogenous c-Src reversibly blocked the activity of the 70-pS K channel in inside-out patches. We conclude that PTK and PTP have no effect on the low-conductance K channels in the mTAL and that PTK-induced tyrosine phosphorylation inhibits, whereas PTP-induced tyrosine dephosphorylation stimulates, the apical 70-pS K channel in the mTAL.

An osteoclastic protein-tyrosine phosphatase regulates the β3-integrin, syk, and shp1 signaling through respective src-dependent phosphorylation in osteoclasts

2012 ◽  
Vol 302 (11) ◽  
pp. C1676-C1686 ◽  
Author(s):  
K.-H. William Lau ◽  
Virginia Stiffel ◽  
Mehran Amoui
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Protein Tyrosine Kinase ◽  
Glutathione Transferase ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Raw264.7 Cells ◽  
Major Protein ◽  
Protein Tyrosine ◽  
Sirna Treatment ◽  
Β3 Integrin

This study utilized the glutathione transferase (GST) pull-down assay to identify novel substrates of an osteoclastic protein-tyrosine phosphatase, PTP-oc. Consistent with the previous findings that the phosphorylated tyr-527 (pY527) of Src is a substrate of PTP-oc, the major protein pulled down with the phosphatase-deficient (PD)-PTP-oc-GST trapping mutant in RAW264.7 cells was Src. The GST-PD-PTP-oc also pulled down pY-Syk and pY-β3-integrin, but not after PP2 pretreatment. However, PTP-oc transgenic osteoclasts or PTP-oc-overexpressing RAW264.7 cells had elevated, and not reduced, levels of pY525/526-Syk and pY759-β3 integrin, and the PTP-oc siRNA treatment drastically reduced levels of pY525/526 Syk and pY759-β3-integrin in RAW264.7 cells. These findings are incompatible with the premise that they are substrates of PTP-oc. The PTP-oc-dependent increases in pY525/526-Syk and pY759-β3-integrin levels were completely blocked by PP2, indicating that these effects are secondary to PTP-oc-mediated activation of the Src protein-tyrosine kinase (PTK). Overexpression of PTP-oc increased, and siRNA-mediated suppression of PTP-oc reduced, pY160-Vav1, pY173-Vav3, and pY783-PLCγ levels, and Rac1 activation, which are downstream mediators of the ITAM/Syk signaling. Overexpression of PTP-oc also increased, and PTP-oc siRNA treatment decreased, the pY-Shp1 levels, which were blocked by PP2. Since Shp1 is a negative regulator of osteoclast activity and is a key mediator of the ITIM signaling, these findings suggest that PTP-oc is an upstream suppressor of the ITIM/Shp1 signaling through PTP-oc-induced Src-dependent Shp1 phosphorylation. In summary, PTP-oc plays a central regulatory role in the concerted regulation of the β3-integrin, the ITAM/Syk, and the ITIM/Shp1 signaling indirectly through activation of Src PTK.

scholarly journals Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK)

2015 ◽  
Vol 112 (14) ◽  
pp. 4495-4500 ◽  
Author(s):  
Dao-Hong Lin ◽  
Peng Yue ◽  
Orlando Yarborough ◽  
Ute I. Scholl ◽  
Gerhard Giebisch ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Phosphatase ◽  
Double Mutant ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
Inhibitory Effect ◽  
Wild Type ◽  
Distal Nephron ◽  
Protein Tyrosine ◽  
Family Protein

With-no-lysine kinase 4 (WNK4) inhibits the activity of the potassium channel KCNJ1 (ROMK) in the distal nephron, thereby contributing to the maintenance of potassium homeostasis. This effect is inhibited via phosphorylation at Ser1196 by serum/glucocorticoid-induced kinase 1 (SGK1), and this inhibition is attenuated by the Src-family protein tyrosine kinase (SFK). Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr1092, Tyr1094, and Tyr1143, and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. Mutation of Tyr1092 or Tyr1143 to phenylalanine decreased the association of c-Src or PTP-1D with WNK4, respectively. Moreover, the Tyr1092Phe mutation markedly reduced ROMK inhibition by WNK4; this inhibition was completely absent in the double mutant WNK4Y1092/1094F. Similarly, c-Src prevented SGK1-induced phosphorylation of WNK4 at Ser1196, an effect that was abrogated in the double mutant. WNK4Y1143F inhibited ROMK activity as potently as wild-type (WT) WNK4, but unlike WT, the inhibitory effect of WNK4Y1143F could not be reversed by SGK1. The failure to reverse WNK4Y1143F-induced inhibition of ROMK by SGK1 was possibly due to enhancing endogenous SFK effect on WNK4 by decreasing the WNK4–PTP-1D association because inhibition of SFK enabled SGK1 to reverse WNK4Y1143F-induced inhibition of ROMK. We conclude that WNK4 is a substrate of SFKs and that the association of c-Src and PTP-1D with WNK4 at Tyr1092 and Tyr1143 plays an important role in modulating the inhibitory effect of WNK4 on ROMK.

scholarly journals The Roles of Pseudophosphatases in Disease

2021 ◽  
Vol 22 (13) ◽  
pp. 6924
Author(s):  
Andrew M. Mattei ◽  
Jonathan D. Smailys ◽  
Emma Marie Wilber Hepworth ◽  
Shantá D. Hinton
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Drug Targets ◽  
Protein Tyrosine Kinase ◽  
Tyrosine Phosphatase ◽  
Signaling Cascades ◽  
Therapeutic Drug ◽  
Protein Tyrosine ◽  
The Past ◽  
Rapid Accumulation ◽  
Bona Fide

The pseudophosphatases, atypical members of the protein tyrosine phosphatase family, have emerged as bona fide signaling regulators within the past two decades. Their roles as regulators have led to a renaissance of the pseudophosphatase and pseudoenyme fields, catapulting interest from a mere curiosity to intriguing and relevant proteins to investigate. Pseudophosphatases make up approximately fourteen percent of the phosphatase family, and are conserved throughout evolution. Pseudophosphatases, along with pseudokinases, are important players in physiology and pathophysiology. These atypical members of the protein tyrosine phosphatase and protein tyrosine kinase superfamily, respectively, are rendered catalytically inactive through mutations within their catalytic active signature motif and/or other important domains required for catalysis. This new interest in the pursuit of the relevant functions of these proteins has resulted in an elucidation of their roles in signaling cascades and diseases. There is a rapid accumulation of knowledge of diseases linked to their dysregulation, such as neuropathies and various cancers. This review analyzes the involvement of pseudophosphatases in diseases, highlighting the function of various role(s) of pseudophosphatases involvement in pathologies, and thus providing a platform to strongly consider them as key therapeutic drug targets.

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