scholarly journals EphA2 is a functional receptor for the growth factor progranulin

2016 ◽  
Vol 215 (5) ◽  
pp. 687-703 ◽  
Author(s):  
Thomas Neill ◽  
Simone Buraschi ◽  
Atul Goyal ◽  
Catherine Sharpe ◽  
Elizabeth Natkanski ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Tyrosine Kinases ◽  
Solid Phase ◽  
Large Family ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Mitogen Activated Protein ◽  
Functional Receptor ◽  
Autoregulatory Mechanism

Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis. Furthermore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an EphA2-dependent manner that was independent of the endocytic receptor sortilin. The discovery of a functional signaling receptor for progranulin offers a new avenue for understanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, and perhaps neurodegenerative diseases.

scholarly journals Role of Phosphoinositide 3-Kinase in Activation of Ras and Mitogen-Activated Protein Kinase by Epidermal Growth Factor

1999 ◽  
Vol 19 (6) ◽  
pp. 4279-4288 ◽  
Author(s):  
Stefan Wennström ◽  
Julian Downward
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Egf Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Ras Activation ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

ABSTRACT The paradigm for activation of Ras and extracellular signal-regulated kinase (ERK)/mitogen-activated protein (MAP) kinase by extracellular stimuli via tyrosine kinases, Shc, Grb2, and Sos does not encompass an obvious role for phosphoinositide (PI) 3-kinase, and yet inhibitors of this lipid kinase family have been shown to block the ERK/MAP kinase signalling pathway under certain circumstances. Here we show that in COS cells activation of both endogenous ERK2 and Ras by low, but not high, concentrations of epidermal growth factor (EGF) is suppressed by PI 3-kinase inhibitors; since Ras activation is less susceptible than ERK2 activation, PI 3-kinase-sensitive events may occur both upstream of Ras and between Ras and ERK2. However, strong elevation of PI 3-kinase lipid product levels by expression of membrane-targeted p110α is by itself never sufficient to activate Ras or ERK2. PI 3-kinase inhibition does not affect EGF-induced receptor autophosphorylation or adapter protein phosphorylation or complex formation. The concentrations of EGF for which PI 3-kinase inhibitors block Ras activation induce formation of Shc-Grb2 complexes but not detectable EGF receptor phosphorylation and do not activate PI 3-kinase. The activation of Ras by low, but mitogenic, concentrations of EGF is therefore dependent on basal, rather than stimulated, PI 3-kinase activity; the inhibitory effects of LY294002 and wortmannin are due to their ability to reduce the activity of PI 3-kinase to below the level in a quiescent cell and reflect a permissive rather than an upstream regulatory role for PI 3-kinase in Ras activation in this system.

scholarly journals ErbB Tyrosine Kinases and the Two Neuregulin Families Constitute a Ligand-Receptor Network

1998 ◽  
Vol 18 (10) ◽  
pp. 6090-6101 ◽  
Author(s):  
Ronit Pinkas-Kramarski ◽  
Maya Shelly ◽  
Bradley C. Guarino ◽  
Ling Mei Wang ◽  
Ljuba Lyass ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Ternary Complex ◽  
Fine Tuning ◽  
Mitogen Activated Protein Kinase ◽  
Receptor Specificity ◽  
Mapk Activation ◽  
Mammary Cell ◽  
Mitogen Activated Protein

ABSTRACT The recently isolated second family of neuregulins, NRG2, shares its primary receptors, ErbB-3 and ErbB-4, and induction of mammary cell differentiation with NRG1 isoforms, suggesting functional redundancy of the two growth factor families. To address this possibility, we analyzed receptor specificity of NRGs by using an engineered cellular system. The activity of isoform-specific but partly overlapping patterns of specificities that collectively activate all eight ligand-stimulatable ErbB dimers was revealed. Specifically, NRG2-β, like NRG1-α, emerges as a narrow-specificity ligand, whereas NRG2-α is a pan-ErbB ligand that binds with different affinities to all receptor combinations, including those containing ErbB-1, but excluding homodimers of ErbB-2. The latter protein, however, displayed cooperativity with the direct NRG receptors. Apparently, signaling by all NRGs is funneled through the mitogen-activated protein kinase (MAPK). However, the duration and potency of MAPK activation depend on the identity of the stimulatory ligand-receptor ternary complex. We conclude that the NRG-ErbB network represents a complex and nonredundant machinery developed for fine-tuning of signal transduction.

scholarly journals Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2.

1996 ◽  
Vol 16 (10) ◽  
pp. 5674-5682 ◽  
Author(s):  
S Corbalan-Garcia ◽  
S S Yang ◽  
K R Degenhardt ◽  
D Bar-Sagi
Keyword(s):  
Growth Factor ◽  
Map Kinase ◽  
Tyrosine Kinases ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Phosphorylation Sites ◽  
Nucleotide Exchange ◽  
Mitogen Activated Protein ◽  
Son Of Sevenless ◽  
Kinase Phosphorylation

The Son of sevenless proteins (Sos) are guanine nucleotide exchange factors involved in the activation of Ras by cytoplasmic and receptor tyrosine kinases. Growth factor stimulation rapidly induces the phosphorylation of Sos on multiple serine and threonine sites. Previous studies have demonstrated that growth factor-induced Sos phosphorylation occurs at the C-terminal region of the protein and is mediated, in part, by mitogen-activated protein (MAP) kinase. In this report, we describe the identification of five MAP kinase sites (S-1137, S-1167, S-1178, S-1193, and S-1197) on hSos1. We demonstrate that four of these sites, S-1132, S-1167, S-1178, and S-1193, become phosphorylated following growth factor stimulation. The MAP kinase phosphorylation sites are clustered within a region encompassing three proline-rich SH3-binding sites in the C-terminal domain of hSos1. Replacing the MAP kinase phosphorylation sites with alanine residues results in an increase in the binding affinity of Grb2 to hSos1. Interestingly, hSos2 contains only one MAP kinase phosphorylation site and, as demonstrated previously, has an increased affinity toward Grb2 compared with hSos1. These results suggest a role for MAP kinase in the regulation of Grb2-Sos interactions. Since the binding of Grb2 is important for Sos function, the phosphorylation-dependent modulation of Grb2-Sos association may provide a means of controlling Ras activation.

Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase

1993 ◽  
Vol 13 (11) ◽  
pp. 7170-7179 ◽  
Author(s):  
J R Fabian ◽  
I O Daar ◽  
D K Morrison
Keyword(s):  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Expression System ◽  
Mitogen Activated Protein Kinase ◽  
Single Amino Acid ◽  
Meiotic Maturation ◽  
Phosphorylation Sites ◽  
Serine Threonine Kinase ◽  
Mitogen Activated Protein

The serine/threonine kinase activity of the Raf-1 proto-oncogene product is stimulated by the activation of many tyrosine kinases, including growth factor receptors and pp60v-src. Recent studies of growth factor signal transduction pathways demonstrate that Raf-1 functions downstream of activated tyrosine kinases and p21ras and upstream of mitogen-activated protein kinase. However, coexpression of both activated tyrosine kinases and p21ras is required for maximal activation of Raf-1 in the baculovirus-Sf9 expression system. In this study, we investigated the role of tyrosine kinases and tyrosine phosphorylation in the regulation of Raf-1 activity. Using the baculovirus-Sf9 expression system, we identified Tyr-340 and Tyr-341 as the major tyrosine phosphorylation sites of Raf-1 when coexpressed with activated tyrosine kinases. Introduction of a negatively charged residue that may mimic the effect of phosphorylation at these sites activated the catalytic activity of Raf-1 and generated proteins that could transform BALB/3T3 cells and induce the meiotic maturation of Xenopus oocytes. In contrast, substitution of noncharged residues that were unable to be phosphorylated produced a protein that could not be enzymatically activated by tyrosine kinases and that could block the meiotic maturation of oocytes induced by components of the receptor tyrosine kinase pathway. These findings demonstrate that maturation of the tyrosine phosphorylation sites can dramatically alter the function of Raf-1. In addition, this is the first report that a transforming Raf-1 protein can be generated by a single amino acid substitution.

scholarly journals Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase.

1993 ◽  
Vol 13 (11) ◽  
pp. 7170-7179 ◽  
Author(s):  
J R Fabian ◽  
I O Daar ◽  
D K Morrison
Keyword(s):  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Expression System ◽  
Mitogen Activated Protein Kinase ◽  
Single Amino Acid ◽  
Meiotic Maturation ◽  
Phosphorylation Sites ◽  
Serine Threonine Kinase ◽  
Mitogen Activated Protein

The serine/threonine kinase activity of the Raf-1 proto-oncogene product is stimulated by the activation of many tyrosine kinases, including growth factor receptors and pp60v-src. Recent studies of growth factor signal transduction pathways demonstrate that Raf-1 functions downstream of activated tyrosine kinases and p21ras and upstream of mitogen-activated protein kinase. However, coexpression of both activated tyrosine kinases and p21ras is required for maximal activation of Raf-1 in the baculovirus-Sf9 expression system. In this study, we investigated the role of tyrosine kinases and tyrosine phosphorylation in the regulation of Raf-1 activity. Using the baculovirus-Sf9 expression system, we identified Tyr-340 and Tyr-341 as the major tyrosine phosphorylation sites of Raf-1 when coexpressed with activated tyrosine kinases. Introduction of a negatively charged residue that may mimic the effect of phosphorylation at these sites activated the catalytic activity of Raf-1 and generated proteins that could transform BALB/3T3 cells and induce the meiotic maturation of Xenopus oocytes. In contrast, substitution of noncharged residues that were unable to be phosphorylated produced a protein that could not be enzymatically activated by tyrosine kinases and that could block the meiotic maturation of oocytes induced by components of the receptor tyrosine kinase pathway. These findings demonstrate that maturation of the tyrosine phosphorylation sites can dramatically alter the function of Raf-1. In addition, this is the first report that a transforming Raf-1 protein can be generated by a single amino acid substitution.

scholarly journals P62dok, a Negative Regulator of Ras and Mitogen-Activated Protein Kinase (Mapk) Activity, Opposes Leukemogenesis by P210bcr-abl

2001 ◽  
Vol 194 (3) ◽  
pp. 275-284 ◽  
Author(s):  
Antonio Di Cristofano ◽  
Masaru Niki ◽  
Mingming Zhao ◽  
Fredrick G. Karnell ◽  
Bayard Clarkson ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinases ◽  
Bone Marrow Cells ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Myelogenous Leukemia ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

p62dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62dok in normal cell signaling as well as in p210bcr-abl leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62dok−/− mice, that the loss of p62dok results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62dok−/− cells after the removal of growth factor. However, p62dok inactivation does not affect DNA damage and growth factor deprivation–induced apoptosis. Furthermore, p62dok inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210bcr-abl in bone marrow cells. These data indicate that p62dok acts as a negative regulator of growth factor–induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62dok can oppose leukemogenesis by p210bcr-abl.

scholarly journals Repetitive Peroxide Exposure Reveals Pleiotropic Mitogen-Activated Protein Kinase Signaling Mechanisms

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Wayne Chadwick ◽  
Alex Keselman ◽  
Sung-Soo Park ◽  
Yu Zhou ◽  
Liyun Wang ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Activity Levels ◽  
Disease Etiology ◽  
Signaling Systems ◽  
Mitogen Activated Protein

Oxidative stressors such as hydrogen peroxide control the activation of many interconnected signaling systems and are implicated in neurodegenerative disease etiology. Application of hydrogen peroxide to PC12 cells activated multiple tyrosine kinases (c-Src, epidermal growth factor receptor (EGFR), and Pyk2) and the serine-threonine kinase ERK1/2. Peroxide-induced ERK1/2 activation was sensitive to intracellular calcium chelation and EGFR and c-Src kinase inhibition. Acute application and removal of peroxide allowed ERK1/2 activity levels to rapidly subside to basal serum-deprived levels. Using this protocol, we demonstrated that ERK1/2 activation tachyphylaxis developed upon repeated peroxide exposures. This tachyphylaxis was independent of c-Src/Pyk2 tyrosine phosphorylation but was associated with a progressive reduction of peroxide-induced EGFR tyrosine phosphorylation, EGFR interaction with growth factor receptor binding protein 2, and a redistribution of EGFR from the plasma membrane to the cytoplasm. Our data indicates that components of peroxide-induced ERK1/2 cascades are differentially affected by repeated exposures, indicating that oxidative signaling may be contextually variable.

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