scholarly journals Protein Tyrosine Phosphatase α (Ptpα) and Contactin Form a Novel Neuronal Receptor Complex Linked to the Intracellular Tyrosine Kinase Fyn

1999 ◽  
Vol 147 (4) ◽  
pp. 707-714 ◽  
Author(s):  
Li Zeng ◽  
Luca D'Alessandri ◽  
Markus B. Kalousek ◽  
Lloyd Vaughan ◽  
Catherine J. Pallen
Keyword(s):  
Cell Surface ◽  
Molecular Mechanisms ◽  
Transmembrane Domain ◽  
Protein Tyrosine Phosphatases ◽  
Nervous System Development ◽  
Cell Surface Receptor ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Receptor Complexes ◽  
Extracellular Region

Glycosyl phosphatidylinositol (GPI)–linked receptors and receptor protein tyrosine phosphatases (RPTPs), both play key roles in nervous system development, although the molecular mechanisms are largely unknown. Despite lacking a transmembrane domain, GPI receptors can recruit intracellular src family tyrosine kinases to receptor complexes. Few ligands for the extracellular regions of RPTPs are known, relegating most to the status of orphan receptors. We demonstrate that PTPα, an RPTP that dephosphorylates and activates src family kinases, forms a novel membrane-spanning complex with the neuronal GPI-anchored receptor contactin. PTPα and contactin associate in a lateral (cis) complex mediated through the extracellular region of PTPα. This complex is stable to isolation from brain lysates or transfected cells through immunoprecipitation and to antibody-induced coclustering of PTPα and contactin within cells. This is the first demonstration of a receptor PTP in a cis configuration with another cell surface receptor, suggesting an additional mode for regulation of a PTP. The transmembrane and catalytic nature of PTPα indicate that it likely forms the transducing element of the complex, and we postulate that the role of contactin is to assemble a phosphorylation-competent system at the cell surface, conferring a dynamic signal transduction capability to the recognition element.

scholarly journals The Cell-Specific Phenotype of the Polymorphic vacA Midregion Is Independent of the Appearance of the Cell Surface Receptor Protein Tyrosine Phosphatase β

2006 ◽  
Vol 74 (1) ◽  
pp. 49-55 ◽  
Author(s):  
David A. G. Skibinski ◽  
Christophe Genisset ◽  
Silvia Barone ◽  
John L. Telford
Keyword(s):  
Cell Surface ◽  
Cell Lines ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Surface Receptor ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Amino Acid Region ◽  
Receptor Protein Tyrosine Phosphatase ◽  
Surface Receptor

ABSTRACT There are two alleles, m1 and m2, of the midregion of the vacuolating cytotoxin gene (vacA) of Helicobacter pylori which code for toxins with different cell specificities. Here we describe the construction of five chimeric strains in which regions of vacA were exchanged between the two genotypes. By analyzing the toxicity of these strains for HeLa and RK13 cells we have confirmed that a 148-amino-acid region determines the phenotypic differences between the two forms of the protein and that this entire region is important for cytotoxicity. Furthermore, we have used our chimeric strains to investigate whether variations in the midregion of VacA have an effect on phorbol 12-myristate 13-acetate (PMA)-induced VacA sensitivity in HL-60 cells. The PMA-induced VacA sensitivity of HL-60 cells has been previously associated with the appearance of the cell surface receptor protein tyrosine phosphatase beta (RPTPβ). Our data indicate that both the m1 and m2 forms of VacA are able to utilize RPTPβ, and the cell-specific phenotype of the midregion is independent of the presence of RPTPβ. It appears that another as-yet-unidentified receptor exists in HL-60 cells that accounts for the m2 phenotype in this cell line. Also, by studying the effect of PMA on levels of RPTPβ in other cell lines and toxicity of VacA in these cell lines we have shown that RPTPβ does not play a major role in the vacuolation of HeLa cells.

PTP-NP, a new member of the receptor protein tyrosine phosphatase family, implicated in development of nervous system and pancreatic endocrine cells

Development ◽  
1996 ◽  
Vol 122 (7) ◽  
pp. 2239-2250 ◽  
Author(s):  
M.K. Chiang ◽  
J.G. Flanagan
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Endocrine Cells ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Receptor Interaction ◽  
Developmental Control ◽  
Protein Tyrosine ◽  
Extracellular Region ◽  
Pancreatic Endocrine Cells

The regulation of protein tyrosine phosphorylation is an important mechanism for developmental control. We describe here a new member of the protein tyrosine phosphatase (PTP) family, called PTP-NP (for neural and pancreatic). The cDNA sequence indicates a receptor-type transmembrane molecule. At early organogenesis, in situ hybridization with a probe for the PTP-NP extracellular region detects expression confined to the region of the developing pancreas, an organ of medical importance, but poorly understood with regard to molecular mechanisms of developmental control. This localized expression appears early, even before morphological differentiation of the pancreas, and is found in presumptive precursors of the endocrine cells by the earliest times that they can be distinguished. In neural development, an alternate RNA with a different or missing extracellular region is expressed transiently at early stages of neurogenesis and the full-length PTP-NP RNA appears later. To search for a ligand of PTP-NP, a fusion protein probe was made with the extracellular domain fused to an alkaline phosphatase tag. This probe bound strongly to pancreatic islets, providing evidence for a ligand-receptor interaction that could be involved in endocrine cell regulation. The results show PTP-NP is an especially early marker for pancreatic development and suggest it may be a receptor that could control the development of pancreatic endocrine cells.

scholarly journals trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors.

1991 ◽  
Vol 11 (1) ◽  
pp. 143-153 ◽  
Author(s):  
D S Middlemas ◽  
R A Lindberg ◽  
T Hunter
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Transmembrane Domain ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Adult Rat ◽  
Trkb Receptors ◽  
Extracellular Region ◽  
Cytoplasmic Tails ◽  
The Brain

We have screened an adult rat cerebellar cDNA library in search of novel protein tyrosine-kinase (PTK) cDNAs. A cDNA for a putative PTK, trkB, was cloned, and its sequence indicates that it is likely to be derived from a gene for a ligand-regulated receptor closely related to the human trk oncogene. Northern (RNA) analysis showed that the trkB gene is expressed predominantly in the brain and that trkB expresses multiple mRNAs, ranging from 0.7 to 9 kb. Hybridization of cerebral mRNAs with a variety of probes indicates that there are mRNAs encoding truncated trkB receptors. Two additional types of cDNA were isolated, and their sequences are predicted to encode two distinct C-terminally truncated receptors which have the complete extracellular region and transmembrane domain, but which differ in their short cytoplasmic tails.

scholarly journals Disrupting the Transmembrane Domain Oligomerization of Protein Tyrosine Phosphatase Receptor J Promotes its Activity in Cancer Cells

2019 ◽  
Author(s):  
Elizabeth Bloch ◽  
Eden L. Sikorski ◽  
David Pontoriero ◽  
Evan K. Day ◽  
Bryan W. Berger ◽  
...  
Keyword(s):  
Structure Function ◽  
Cancer Cells ◽  
Transmembrane Domain ◽  
Human Cancer ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatases ◽  
Receptor Protein ◽  
Structural Basis ◽  
Protein Tyrosine ◽  
In Cells

Despite the critical regulatory roles that receptor protein tyrosine phosphatases (RPTP) play in mammalian signal transduction, the detailed structural basis for the regulation of their catalytic activity is not fully understood, nor are they generally therapeutically targetable. It is due, in part, to the lack of known natural ligands or selective agonists. In contrast to conventional structure-function relationship for receptor tyrosine kinases (RTKs), the activity of RPTPs has been reported to be suppressed by dimerization, which may prevent their access to their RTK substrates. We report here that: (i) homodimerization of PTPRJ (also known as DEP-1) is regulated by specific transmembrane (TM) residues, and (ii) disrupting these interactions can destabilize full-length PTPRJ homodimerization in cells, reduce the phosphorylation of EGFR (a known substrate) and downstream signaling effectors, antagonize EGFR-driven cell phenotypes, and promote substrate access. We demonstrate these points in human cancer cells using both mutational studies and through the identification of a peptide designed to bind to the PTPRJ TM domain. This peptide is the first example of such allosteric agonist of RPTPs. This study, therefore, provides not only fundamental structure-function insights on how PTPRJ activity is tuned by TM interactions in cells but also opportunities to develop a unique class of agents that could be used as tools to probe RPTPs signaling regulating mechanisms or for therapeutic purposes in cancers driven by RTK signaling.

scholarly journals Receptor-Like Protein Tyrosine Phosphatase α Homodimerizes on the Cell Surface

2000 ◽  
Vol 20 (16) ◽  
pp. 5917-5929 ◽  
Author(s):  
Guoqiang Jiang ◽  
Jeroen den Hertog ◽  
Tony Hunter
Keyword(s):  
Biological Activity ◽  
Cell Surface ◽  
Protein Tyrosine Phosphatase ◽  
Intracellular Signaling ◽  
Catalytic Domain ◽  
Transmembrane Domain ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Dependent Manner ◽  
Protein Tyrosine

ABSTRACT We reported previously that the N-terminal D1 catalytic domain of receptor protein-tyrosine phosphatase α (RPTPα) forms a symmetrical, inhibited dimer in a crystal structure, in which a helix-turn-helix wedge element from one monomer is inserted into the catalytic cleft of the other monomer. Previous functional studies also suggested that dimerization inhibits the biological activity of a CD45 chimeric RPTP and the catalytic activity of an isolated RPTPς D1 catalytic domain. Most recently, we have also shown that enforced dimerization inhibits the biological activity of full-length RPTPα in a wedge-dependent manner. The physiological significance of such inhibition is unknown, due to a lack of understanding of how RPTPα dimerization is regulated in vivo. In this study, we show that transiently expressed cell surface RPTPα exists predominantly as homodimers, suggesting that dimerization-mediated inhibition of RPTPα biological activity is likely to be physiologically relevant. Consistent with our published and unpublished crystallographic data, we show that mutations in the wedge region of D1 catalytic domain and deletion of the entire D2 catalytic domain independently reduced but did not abolish RPTPα homodimerization, suggesting that both domains are critically involved but that neither is essential for homodimerization. Finally, we also provide evidence that both the RPTPα extracellular domain and the transmembrane domain were independently able to homodimerize. These results lead us to propose a zipper model in which inactive RPTPα dimers are stabilized by multiple, relatively weak dimerization interfaces. Dimerization in this manner would provide a potential mechanism for negative regulation of RPTPα. Such RPTPα dimers could be activated by extracellular ligands or intracellular binding proteins that induce monomerization or by intracellular signaling events that induce an open conformation of the dimer.

Receptor Protein Tyrosine Phosphatases in Nervous System Development

2003 ◽  
Vol 83 (1) ◽  
pp. 1-24 ◽  
Author(s):  
Karl G. Johnson ◽  
David Van Vactor
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Crystal Structures ◽  
System Development ◽  
Protein Tyrosine Phosphatases ◽  
Nervous System Development ◽  
Receptor Protein ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatases

Receptor protein tyrosine phosphatases (RPTPs) are key regulators of neuronal morphogenesis in a variety of different vertebrate and invertebrate systems, yet the mechanisms by which these proteins regulate central nervous system development are poorly understood. In the past few years, studies have begun to outline possible models for RPTP function by demonstrating in vivo roles for RPTPs in axon outgrowth, guidance, and synaptogenesis. In addition, the crystal structures of several RPTPs have been solved, numerous downstream effectors of RPTP signaling have been identified, and a small number of RPTP ligands have been described. In this review, we focus on how RPTPs transduce signals from the extracellular environment to the cytoplasm, using a detailed comparative analysis of the different RPTP subfamilies. Focusing on the roles RPTPs play in the development of the central nervous system, we discuss how the elucidation of RPTP crystal structures, the biochemical analysis of phosphatase enzyme catalysis, and the characterization of complex signal transduction cascades downstream of RPTPs have generated testable models of RPTP structure and function.

Receptor protein tyrosine phosphatase μ: measuring where to stick

2008 ◽  
Vol 36 (2) ◽  
pp. 167-172 ◽  
Author(s):  
A. Radu Aricescu ◽  
Christian Siebold ◽  
E. Yvonne Jones
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Surface Receptor ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatase ◽  
Extracellular Region ◽  
Fibronectin Type Iii ◽  
Surface Receptor ◽  
And Function

We review here recent results on the structure and function of a receptor protein tyrosine phosphatase, RPTPμ. In addition to their intercellular catalytic domains which bear the phosphatase activity, the RPTPs are cell-surface-receptor-type molecules and in many cases have large extracellular regions. What role can these extracellular regions play in function? For RPTPμ, the extracellular region is known to mediate homophilic adhesion. Sequence analysis indicates that it comprises six domains: an N-terminal MAM (meprin/A5/μ), one immunoglobulin-like domain and four fibronectin type III (FN) repeats. We have determined the crystal structure of the entire extracellular region for RPTPμ in the form of a functional adhesion dimer. The physical characteristics and dimensions of the adhesion dimer suggest a mechanism by which the location of this phosphatase can be influenced by cell–cell spacings.

trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors

1991 ◽  
Vol 11 (1) ◽  
pp. 143-153
Author(s):  
D S Middlemas ◽  
R A Lindberg ◽  
T Hunter
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Transmembrane Domain ◽  
Receptor Protein ◽  
Protein Tyrosine ◽  
Adult Rat ◽  
Trkb Receptors ◽  
Extracellular Region ◽  
Cytoplasmic Tails ◽  
The Brain

We have screened an adult rat cerebellar cDNA library in search of novel protein tyrosine-kinase (PTK) cDNAs. A cDNA for a putative PTK, trkB, was cloned, and its sequence indicates that it is likely to be derived from a gene for a ligand-regulated receptor closely related to the human trk oncogene. Northern (RNA) analysis showed that the trkB gene is expressed predominantly in the brain and that trkB expresses multiple mRNAs, ranging from 0.7 to 9 kb. Hybridization of cerebral mRNAs with a variety of probes indicates that there are mRNAs encoding truncated trkB receptors. Two additional types of cDNA were isolated, and their sequences are predicted to encode two distinct C-terminally truncated receptors which have the complete extracellular region and transmembrane domain, but which differ in their short cytoplasmic tails.

scholarly journals Down-Regulation of Cell Surface Receptors Is Modulated by Polar Residues within the Transmembrane Domain

2000 ◽  
Vol 11 (8) ◽  
pp. 2643-2655 ◽  
Author(s):  
Lolita Zaliauskiene ◽  
Sunghyun Kang ◽  
Christie G. Brouillette ◽  
Jacob Lebowitz ◽  
Ramin B. Arani ◽  
...  
Keyword(s):  
Cell Surface ◽  
Transmembrane Domain ◽  
Gradient Centrifugation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Surface Proteins ◽  
Down Regulation ◽  
Surface Receptors ◽  
Receptor Complexes ◽  
Polar Residues

How recycling receptors are segregated from down-regulated receptors in the endosome is unknown. In previous studies, we demonstrated that substitutions in the transferrin receptor (TR) transmembrane domain (TM) convert the protein from an efficiently recycling receptor to one that is rapidly down regulated. In this study, we demonstrate that the “signal” within the TM necessary and sufficient for down-regulation is Thr11Gln17Thr19 (numbering in TM). Transplantation of these polar residues into the wild-type TR promotes receptor down-regulation that can be demonstrated by changes in protein half-life and in receptor recycling. Surprisingly, this modification dramatically increases the TR internalization rate as well (∼79% increase). Sucrose gradient centrifugation and cross-linking studies reveal that propensity of the receptors to self-associate correlates with down-regulation. Interestingly, a number of cell surface proteins that contain TM polar residues are known to be efficiently down-regulated, whereas recycling receptors for low-density lipoprotein and transferrin conspicuously lack these residues. Our data, therefore, suggest a simple model in which specific residues within the TM sequences dramatically influence the fate of membrane proteins after endocytosis, providing an alternative signal for down-regulation of receptor complexes to the well-characterized cytoplasmic tail targeting signals.

scholarly journals Characterization of a cDNA encoding a cysteine-rich cell surface protein located in the flagellar pocket of the protozoan Trypanosoma brucei.

1990 ◽  
Vol 10 (9) ◽  
pp. 4506-4517 ◽  
Author(s):  
M G Lee ◽  
B E Bihain ◽  
D G Russell ◽  
R J Deckelbaum ◽  
L H Van der Ploeg
Keyword(s):  
Amino Acid ◽  
Cell Surface ◽  
Trypanosoma Brucei ◽  
Transmembrane Domain ◽  
Density Lipoprotein ◽  
Surface Protein ◽  
Integral Membrane Protein ◽  
Cell Surface Receptor ◽  
Flagellar Pocket ◽  
Cytoplasmic Extension

We have characterized a cDNA encoding a cysteine-rich, acidic integral membrane protein (CRAM) of the parasitic protozoa Trypanosoma brucei and Trypanosoma equiperdum. Unlike other membrane proteins of T. brucei, which are distributed throughout the cell surface, CRAM is concentrated in the flagellar pocket, an invagination of the cell surface of the trypanosome where endocytosis has been documented. Accordingly, CRAM also locates to vesicles located underneath the pocket, providing evidence of its internalization. CRAM has a predicted molecular mass of 130 kilodaltons and has a signal peptide, a transmembrane domain, and a 41-amino-acid cytoplasmic extension. A characteristic feature of CRAM is a large extracellular domain with a roughly 66-fold acidic, cysteine-rich 12-amino-acid repeat. CRAM is conserved among different protozoan species, including Trypanosoma cruzi, and CRAM has structural similarities with eucaryotic cell surface receptors. The most striking homology of CRAM is to the human low-density-lipoprotein receptor. We propose that CRAM functions as a cell surface receptor of different trypanosome species.

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