Membrane-targeting is critical for the phosphorylation of Vav2 by activated EGF receptor

Tamás, Péter; Solti, Zita; Buday, László

doi:10.1016/s0898-6568(01)00172-3

Cited by 19 publications

(11 citation statements)

References 23 publications

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“…For example, when ectopically expressed in nonhematopoietic cells, Vav1 associates with the EGFR through its SH2 region and becomes tyrosine phosphorylated upon induction with EGF (Bustelo et al, 1992;Margolis et al, 1992;Katzav, 1993). A similar result was reported for the ubiquitously expressed Vav2 (Pandey et al, 2000;Tamas et al, 2001Tamas et al, , 2003 and Vav3 proteins (Zeng et al, 2000). Although it is well established that the Vav proteins are tyrosine phosphorylated upon EGFR stimulation, the exact contribution of the various mammalian Vav proteins to the EGFR signalling pathway is not understood.…”

Section: Discussionmentioning

confidence: 54%

DroVav, the Drosophila melanogaster homologue of the mammalian Vav proteins, serves as a signal transducer protein in the Rac and DER pathways

2003

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Mammalian Vav signal transducer proteins couple receptor tyrosine kinase signals to the activation of the Rho/Rac GTPases, leading to cell differentiation and/or proliferation. The unique and complex structure of mammalian Vav proteins is preserved in the Drosophila melanogaster homologue, DroVav. We demonstrate that DroVav functions as a guanine-nucleotide exchange factor (GEF) for DRac. Drosophila cells overexpressing wildtype (wt) DroVav exhibited a normal morphology. However, overexpression of a truncated DroVav mutant (that functions as an oncogene when expressed in NIH3T3 cells) results in striking changes in the actin cytoskeleton, resembling those usually visible following Rac activation. Dominant-negative DRac abrogated these morphological changes, suggesting that the effect of the truncated DroVav mutant is mediated by activation of DRac. In Drosophila cells, we find that stimulation of the Drosophila EGF receptor (DER) increases tyrosine phosphorylation of DroVav, which in turn associates with tyrosine-phosphorylated DER. In addition, the following results imply that DroVav participates in downstream DER signalling, such as ERK phosphorylation: (a) overexpression of DroVav induces ERK phosphorylation; and (b) 'knockout' of DroVav by RNA interference blocks ERK phosphorylation induced by DER stimulation. Unlike mammalian Vav proteins, DroVav was not found to induce Jnk phosphorylation under the experimental circumstances tested in fly cells. These results establish the role of DroVav as a signal transducer that participates in receptor tyrosine kinase pathways and functions as a GEF for the small RhoGTPase, DRac.

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Section: Discussionmentioning

confidence: 54%

DroVav, the Drosophila melanogaster homologue of the mammalian Vav proteins, serves as a signal transducer protein in the Rac and DER pathways

2003

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“…Second, the nature of siKALIP requires sufficient activity of purified kinase in vitro. The reconstitution of purified kinase assay in vitro may require a prerequisite activation event (58), cofactor (59), or cellular context (60). Third, a full spectrum of kinase-dependent phosphorylation change in vivo is essential.…”

Section: Identifying Direct Substrate Of Erk1 Under the Physiologicalmentioning

confidence: 99%

Identification of Extracellular Signal-regulated Kinase 1 (ERK1) Direct Substrates using Stable Isotope Labeled Kinase Assay-Linked Phosphoproteomics

Xue¹,

Wang²,

Cao³

et al. 2014

Molecular & Cellular Proteomics

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Kinase mediated phosphorylation signaling is extensively involved in cellular functions and human diseases, and unraveling phosphorylation networks requires the identification of substrates targeted by kinases, which has remained challenging. We report here a novel proteomic strategy to identify the specificity and direct substrates of kinases by coupling phosphoproteomics with a sensitive stable isotope labeled kinase reaction. A whole cell extract was moderately dephosphorylated and subjected to in vitro kinase reaction under the condition in which 18 O-ATP is the phosphate donor. The phosphorylated proteins are then isolated and identified by mass spectrometry, in which the heavy phosphate (؉85.979 Da) labeled phosphopeptides reveal the kinase specificity. The in vitro phosphorylated proteins with heavy phosphates are further overlapped with in vivo kinase-dependent phosphoproteins for the identification of direct substrates with high confidence. The strategy allowed us to identify 46 phosphorylation sites on 38 direct substrates of extracellular signal-regulated kinase 1, including multiple known substrates and novel substrates, highlighting the ability of this high throughput method for direct kinase substrate screening. Molecular & Cellular

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“…Residues-It has been well documented that EGF receptor can phosphorylate Vav2 in intact cells (11)(12)(13)(14)25). López-Lago et al (12) have shown recently that tyrosine kinase Lck can phosphorylate all potential tyrosine residues (Tyr-142, Tyr-160, Tyr-174) in the N-terminal domain of Vav1.…”

Section: Epidermal Growth Factor Stimulates Phosphorylation Of Vav2 Omentioning

confidence: 99%

Mechanism of Epidermal Growth Factor Regulation of Vav2, a Guanine Nucleotide Exchange Factor for Rac

Tamás¹,

Solti²,

Bauer³

et al. 2003

Journal of Biological Chemistry

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104

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Membrane-targeting is critical for the phosphorylation of Vav2 by activated EGF receptor

Cited by 19 publications

References 23 publications

DroVav, the Drosophila melanogaster homologue of the mammalian Vav proteins, serves as a signal transducer protein in the Rac and DER pathways

DroVav, the Drosophila melanogaster homologue of the mammalian Vav proteins, serves as a signal transducer protein in the Rac and DER pathways

Identification of Extracellular Signal-regulated Kinase 1 (ERK1) Direct Substrates using Stable Isotope Labeled Kinase Assay-Linked Phosphoproteomics

Mechanism of Epidermal Growth Factor Regulation of Vav2, a Guanine Nucleotide Exchange Factor for Rac

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