PRV-1 Interacts with the Cytoplasmic Domain of Mpl and Interferes with TPO-Induced Signaling Cascades.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1160-1160 ◽  
Author(s):  
Jan Johnson ◽  
Manish Ghandi ◽  
Jennifer N. Minear ◽  
Brian J. Lannutti
Keyword(s):  
Myeloproliferative Disorders ◽  
Cytoplasmic Domain ◽  
Mapk Signaling ◽  
Signaling Cascades ◽  
Cytokine Signaling ◽  
Amino Acid Residues ◽  
Surface Receptors ◽  
Cytoplasmic Region ◽  
Physiological Relevance ◽  
And Function

Abstract Polycythemia rubra vera-1 (PRV-1) is a member of the uPAR/CD59/Ly6 family of cell surface receptors. An increase in the expression level of PRV-1 mRNA has been shown in patients with polycythemia vera and essential thrombocythemia, however, the ligand and function of PRV-1 remains unclear. Here, we show for the first time that PRV-1 expression alters the TPO-mediated Mpl receptor-signaling pathway. We also report a novel interaction between PRV-1 and the cytoplasmic region of Mpl (121 amino acids) using a yeast two-hybrid screen. Further characterization of this interaction in yeast containing truncated versions of the Mpl receptor cytoplasmic region indicates that the binding of PRV-1 to Mpl is regulated at the distal end of the cytoplasmic region. Deletion analysis utilizing Mpl receptors truncated after 53 (T53) or 69 (T69) cytoplasmic amino acid residues failed to show an association with PRV-1. Further mapping of the cytoplasmic domain of Mpl showed that truncations equal or greater than 111 cytoplasmic residues (T111) restored the interaction with PRV-1. To examine the physiological relevance of this interaction, we co-expressed Mpl and PRV-1 in BaF3 cells. Western blot analysis with an anti-phosphotyrosine antibody on TPO-stimulated BaF3/Mpl/PRV-1 whole cell lysates demonstrated a noticeable change in intracellular phosphorylation when compared to BaF3/Mpl. We found no affect on Jak2 and Mpl tyrosine phosphorylation. In contrast, there were higher levels of tyrosine-phosphorylated STAT5 and STAT3 in BaF3/Mpl cells expressing PRV-1. We then further investigated the effect of PRV-1 expression on MAPK signaling. We found that TPO-stimulation of BaF3/Mpl/PRV-1 cells resulted in a reduction of MAPK phosphorylation compared with cells expressing Mpl alone. These results indicate a novel function for PRV-1 as a signaling molecule in cytokine signaling cascades and may lead to a greater understanding of the mechanism of overexpression of PRV-1 in myeloproliferative disorders.

scholarly journals Amino Acid Residues in the Cytoplasmic Domain of the Mason-Pfizer Monkey Virus Glycoprotein Critical for Its Incorporation into Virions

2005 ◽  
Vol 79 (18) ◽  
pp. 11559-11568 ◽  
Author(s):  
Chisu Song ◽  
Keith Micoli ◽  
Helena Bauerova ◽  
Iva Pichova ◽  
Eric Hunter
Keyword(s):  
Amino Acid ◽  
Transmembrane Protein ◽  
Critical Role ◽  
Cytoplasmic Domain ◽  
Virus Infectivity ◽  
Amino Acid Residues ◽  
Glycoprotein Complex ◽  
Uptake Studies ◽  
Domain Block ◽  
And Function

ABSTRACT Assembly of an infectious retrovirus requires the incorporation of the envelope glycoprotein complex during the process of particle budding. We have recently demonstrated that amino acid substitutions of a tyrosine residue in the cytoplasmic domain block glycoprotein incorporation into budding Mason-Pfizer monkey virus (M-PMV) particles and abrogate infectivity (C. Song, S. R. Dubay, and E. Hunter, J. Virol. 77:5192-5200, 2003). To investigate the contribution of other amino acids in the cytoplasmic domain to the process of glycoprotein incorporation, we introduced alanine-scanning mutations into this region of the transmembrane protein. The effects of the mutations on glycoprotein biosynthesis and function, as well as on virus infectivity, have been examined. Mutation of two cytoplasmic residues, valine 20 and histidine 21, inhibits viral protease-mediated cleavage of the cytoplasmic domain that is observed during virion maturation, but the mutant virions show only moderately reduced infectivity. We also demonstrate that the cytoplasmic domain of the M-PMV contains three amino acid residues that are absolutely essential for incorporation of glycoprotein into virions. In addition to the previously identified tyrosine at residue 22, an isoleucine at position 18 and a leucine at position 25 each mediate the process of incorporation and efficient release of virions. While isoleucine 18 may be involved in direct interactions with immature capsids, antibody uptake studies showed that leucine 25 and tyrosine 22 are part of an efficient internalization signal in the cytoplasmic domain of the M-PMV glycoprotein. These results demonstrate that the cytoplasmic domain of M-PMV Env, in part through its YXXL-mediated endocytosis and intracellular trafficking signals, plays a critical role in the incorporation of glycoprotein into virions.

scholarly journals The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4000
Author(s):  
Esra’a Keewan ◽  
Ksenia Matlawska-Wasowska
Keyword(s):  
Intracellular Signaling ◽  
Cell Communication ◽  
Janus Kinase ◽  
Signaling Cascades ◽  
Cytokine Signaling ◽  
Surface Receptors ◽  
Wide Range ◽  
Stat Signaling ◽  
Leukemia Development

Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.

scholarly journals Requirements for the cytoplasmic domain of the alphaPS1, alphaPS2 and betaPS integrin subunits during Drosophila development

Development ◽  
1998 ◽  
Vol 125 (4) ◽  
pp. 701-711
Author(s):  
X. Li ◽  
M.W. Graner ◽  
E.L. Williams ◽  
C.E. Roote ◽  
T.A. Bunch ◽  
...  
Keyword(s):  
Temperature Shift ◽  
Cytoplasmic Tail ◽  
Cytoplasmic Domain ◽  
Amino Acid Residues ◽  
Cytoplasmic Domains ◽  
Mutant Proteins ◽  
Adhesive Interactions ◽  
And Function ◽  
The Relationship ◽  
Tail Function

The integrins are a family of transmembrane heterodimeric proteins that mediate adhesive interactions and participate in signaling across the plasma membrane. In this study we examine the functional significance of the cytoplasmic domains of the alphaPS1, alphaPS2 and betaPS subunits of the Drosophila Position Specific (PS) integrin family by analyzing the relationship between cytoplasmic domain structure and function in the context of a developing organism. By examining the ability of ssPS molecules lacking the cytoplasmic domain to rescue embryonic abnormalities associated with PS integrin loss, we find that although many embryonic events require the betaPS cytoplasmic domain, this portion of the molecule is not required for at least two processes requiring PS integrins: formation of midgut constrictions and maintaining germband integrity. Furthermore, our studies demonstrate that mutant proteins affecting four highly conserved amino acid residues in the cytoplasmic tail function with different efficiencies during embryonic development, suggesting that interaction of PS integrins with cytoplasmic ligands is developmentally modulated during embryogenesis. We have also examined the ability of alphaPS1 and alphaPS2 to function without their cytoplasmic domains. By analyzing the ability of transgenes producing truncated alphaPS molecules to rescue abnormalities associated with integrin loss, we find that the cytoplasmic tail of alphaPS2 is essential for both embryonic and postembryonic processes, while this portion of alphaPS1 is not required for function in the wing and in the retina. Furthermore, temperature-shift experiments suggest roles for the alphaPS2 cytoplasmic domain in signaling events occurring in the developing wing.

Extracellular matrix: the gatekeeper of tumor angiogenesis

2019 ◽  
Vol 47 (5) ◽  
pp. 1543-1555 ◽  
Author(s):  
Maurizio Mongiat ◽  
Simone Buraschi ◽  
Eva Andreuzzi ◽  
Thomas Neill ◽  
Renato V. Iozzo
Keyword(s):  
Extracellular Matrix ◽  
Tumor Angiogenesis ◽  
Signaling Cascades ◽  
Cancer Growth ◽  
Cell Behavior ◽  
Metastatic Progression ◽  
Surface Receptors ◽  
The Matrix ◽  
Multiple Signaling

Abstract The extracellular matrix is a network of secreted macromolecules that provides a harmonious meshwork for the growth and homeostatic development of organisms. It conveys multiple signaling cascades affecting specific surface receptors that impact cell behavior. During cancer growth, this bioactive meshwork is remodeled and enriched in newly formed blood vessels, which provide nutrients and oxygen to the growing tumor cells. Remodeling of the tumor microenvironment leads to the formation of bioactive fragments that may have a distinct function from their parent molecules, and the balance among these factors directly influence cell viability and metastatic progression. Indeed, the matrix acts as a gatekeeper by regulating the access of cancer cells to nutrients. Here, we will critically evaluate the role of selected matrix constituents in regulating tumor angiogenesis and provide up-to-date information concerning their primary mechanisms of action.

scholarly journals A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction.

1994 ◽  
Vol 14 (11) ◽  
pp. 7404-7413 ◽  
Author(s):  
S Takaki ◽  
H Kanazawa ◽  
M Shiiba ◽  
K Takatsu
Keyword(s):  
Signal Transduction ◽  
Protein Tyrosine Kinase ◽  
Cytoplasmic Domain ◽  
Beta Chain ◽  
Cytoplasmic Domains ◽  
Interleukin 5 ◽  
Alpha Chain ◽  
Gm Csf ◽  
Response Expression ◽  
And Function

Interleukin-5 (IL-5) regulates the production and function of B cells, eosinophils, and basophils. The IL-5 receptor (IL-5R) consists of two distinct membrane proteins, alpha and beta. The alpha chain (IL-5R alpha) is specific to IL-5. The beta chain is the common beta chain (beta c) of receptors for IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF). The cytoplasmic domains of both alpha and beta chains are essential for signal transduction. In this study, we generated cDNAs of IL-5R alpha having various mutations in their cytoplasmic domains and examined the function of these mutants by expressing them in IL-3-dependent FDC-P1 cells. The membrane-proximal proline-rich sequence of the cytoplasmic domain of IL-5R alpha, which is conserved among the alpha chains of IL-5R, IL-3R, and GM-CSF receptor (GM-CSFR), was found to be essential for the IL-5-induced proliferative response, expression of nuclear proto-oncogenes such as c-jun, c-fos, and c-myc, and tyrosine phosphorylation of cellular proteins including JAK2 protein-tyrosine kinase. In addition, analysis using chimeric receptors which consist of the extracellular domain of IL-5R alpha and the cytoplasmic domain of beta c suggested that dimerization of the cytoplasmic domain of beta c may be an important step in activating the IL-5R complex and transducing intracellular growth signals.

Chitosanase from Streptomyces sp. strain N174: a comparative review of its structure and function

1997 ◽  
Vol 75 (6) ◽  
pp. 687-696 ◽  
Author(s):  
Tamo Fukamizo ◽  
Ryszard Brzezinski
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Substrate Binding ◽  
Structure And Function ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Streptomyces Sp ◽  
Binding Cleft ◽  
And Function

Novel information on the structure and function of chitosanase, which hydrolyzes the beta -1,4-glycosidic linkage of chitosan, has accumulated in recent years. The cloning of the chitosanase gene from Streptomyces sp. strain N174 and the establishment of an efficient expression system using Streptomyces lividans TK24 have contributed to these advances. Amino acid sequence comparisons of the chitosanases that have been sequenced to date revealed a significant homology in the N-terminal module. From energy minimization based on the X-ray crystal structure of Streptomyces sp. strain N174 chitosanase, the substrate binding cleft of this enzyme was estimated to be composed of six monosaccharide binding subsites. The hydrolytic reaction takes place at the center of the binding cleft with an inverting mechanism. Site-directed mutagenesis of the carboxylic amino acid residues that are conserved revealed that Glu-22 and Asp-40 are the catalytic residues. The tryptophan residues in the chitosanase do not participate directly in the substrate binding but stabilize the protein structure by interacting with hydrophobic and carboxylic side chains of the other amino acid residues. Structural and functional similarities were found between chitosanase, barley chitinase, bacteriophage T4 lysozyme, and goose egg white lysozyme, even though these proteins share no sequence similarities. This information can be helpful for the design of new chitinolytic enzymes that can be applied to carbohydrate engineering, biological control of phytopathogens, and other fields including chitinous polysaccharide degradation. Key words: chitosanase, amino acid sequence, overexpression system, reaction mechanism, site-directed mutagenesis.

scholarly journals A Tyrosine Motif in the Cytoplasmic Domain of Mason-Pfizer Monkey Virus Is Essential for the Incorporation of Glycoprotein into Virions

2003 ◽  
Vol 77 (9) ◽  
pp. 5192-5200 ◽  
Author(s):  
Chisu Song ◽  
Susan R. Dubay ◽  
Eric Hunter
Keyword(s):  
Amino Acid ◽  
Cytoplasmic Domain ◽  
Virus Infectivity ◽  
Fusion Activity ◽  
Tyrosine Residues ◽  
Glycoprotein Complex ◽  
Selective Incorporation ◽  
Uptake Studies ◽  
And Function ◽  
Immature Virus

ABSTRACT Mason-Pfizer monkey virus (M-PMV) encodes a transmembrane (TM) glycoprotein with a 38-amino-acid-long cytoplasmic domain. After the release of the immature virus, a viral protease-mediated cleavage occurs within the cytoplasmic domain, resulting in the loss of 17 amino acids from the carboxy terminus. This maturational cleavage occurs between a histidine at position 21 and a tyrosine at position 22 in the cytoplasmic domain of the TM protein. We have demonstrated previously that a truncated TM glycoprotein with a 21-amino-acid-long cytoplasmic tail showed enhanced fusogenicity but could not be incorporated into virions. These results suggest that postassembly cleavage of the cytoplasmic domain removes a necessary incorporation signal and activates fusion activity. To investigate the contribution of tyrosine residues to the function of the glycoprotein complex and virus replication, we have introduced amino acid substitutions into two tyrosine residues found in the cytoplasmic domain. The effects of these mutations on glycoprotein biosynthesis and function, as well as on virus infectivity, have been examined. Mutation of tyrosine 34 to alanine had little effect on glycoprotein function. In contrast, substitutions at tyrosine 22 modulated fusion activity in either a positive or negative manner, depending on the substituting amino acid. Moreover, any nonaromatic substitution at this position blocked glycoprotein incorporation into virions and abolished infectivity. These results demonstrate that M-PMV employs a tyrosine signal for the selective incorporation of glycoprotein into budding virions. Antibody uptake studies show that tyrosine 22 is part of an efficient internalization signal in the cytoplasmic domain of the M-PMV glycoprotein that can also be positively and negatively influenced by changes at this site.

Biology of bone marrow-derived endothelial cell precursors

2007 ◽  
Vol 292 (1) ◽  
pp. H1-H18 ◽  
Author(s):  
Gina C. Schatteman ◽  
Martine Dunnwald ◽  
Chunhua Jiao
Keyword(s):  
Bone Marrow ◽  
Endothelial Cell ◽  
Marrow Cell ◽  
Tumor Type ◽  
Physiological Relevance ◽  
Bone Marrow Derived Cells ◽  
And Function ◽  
Endothelial Nitric Oxide ◽  
The Impact ◽  
Endothelial Precursors

Over the past decade, the old idea that the bone marrow contains endothelial cell precursors has become an area of renewed interest. While some still believe that there are no endothelial precursors in the blood, even among those who do, there is no consensus as to what they are or what they do. In this review, we describe the problems in identifying endothelial cells and conclude that expression of endothelial nitric oxide synthase may be the most reliable antigenic indicator of the phenotype. The evidence for two different classes of endothelial precursors is also presented. We suggest that, though there is no single endothelial cell precursor, we may be able to use these phenotypic variations to our advantage in better understanding their biology. We also discuss how a variety of genetic, epigenetic, and methodological differences can account for the seemingly contradictory findings on the physiological relevance of bone marrow-derived precursors in normal vascular maintenance and in response to injury. Data on the impact of tumor type and location on the contribution of bone marrow-derived cells to the tumor vasculature are also presented. These data provide hope that we may ultimately be able to predict those tumors in which bone marrow-derived cells will have a significant contribution and design therapies accordingly. Finally, factors that regulate bone marrow cell recruitment to and function in the endothelium are beginning to be identified, and several of these, including stromal derived factor 1, monocyte chemoattractant factor-1, and vascular endothelial growth factor are discussed.

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