Adaptor ShcA Protein Binds Tyrosine Kinase Tie2 Receptor and Regulates Migration and Sprouting but Not Survival of Endothelial Cells

Audero, Enrica; Cascone, Ilaria; Maniero, Fabrizio; Napione, Lucia; Arese, Marco; Lanfrancone, Luisa; Bussolino, Federico

doi:10.1074/jbc.m307456200

Cited by 44 publications

(44 citation statements)

References 68 publications

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“…7 AKT is involved in the prosurvival and angiogenic activities of Ang-1. 8 Interaction of ShcA with Tie2 and phospholipase D-dependent regulation of mitogen-activated protein kinase (MAPK) are involved in Ang-1-mediated cell migration 9 and a Ras/MAPK cascade is responsible for Ang-1-induced cell proliferation. 10 We have shown that Ang-1 inhibits thrombin-induced activation of Rho-and Ca 2ϩ -dependent pathways, together with a newly described protein kinase C (PKC) -dependent signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Basal and angiopoietin-1–mediated endothelial permeability is regulated by sphingosine kinase-1

Stanković

Bonder

et al. 2008

Blood

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Endothelial cells (ECs) regulate the barrier function of blood vessels. Here we show that basal and angiopoietin-1 (Ang-1)-regulated control of EC permeability is mediated by 2 different functional states of sphingosine kinase-1 (SK-1). Mice depleted of SK-1 have increased vascular leakiness, whereas mice transgenic for SK-1 in ECs show attenuation of leakiness. Furthermore, Ang-1 rapidly and transiently stimulates SK-1 activity and phosphorylation, and induces an increase in intracellular sphingosine-1-phosphate (S1P) concentration. Overexpression of SK-1 resulted in inhibition of permeability similar to that seen for Ang-1, whereas knockdown of SK-1 by small interfering RNA blocked Ang-1-mediated inhibition of permeability. Transfection with SK S225A , a nonphosphorylatable mutant of SK-1, inhibited basal leakiness, and both SK S225A and a dominant-negative SK-1 mutant removed the capacity of Ang-1 to inhibit permeability. These effects were independent of extracellular S1P as knockdown or inhibition of S1P 1 , S1P 2 , or S1P 3 , did not affect the Ang-1 response. Thus, SK-1 levels in ECs powerfully regulate basal permeability in vitro and in vivo. In addition, the Ang-1-induced inhibition of leakiness is mediated through activation of SK-1, defining a new signaling pathway in the Ang-1 regulation of permeability. IntroductionThe control of vascular homeostasis is mediated through the maintenance of endothelial cell (EC) monolayer integrity, which is responsible for the tonic impermeable nature of blood vessels. Altered endothelial integrity underlies changes in vascular permeability, as seen in inflammatory responses and angiogenesis, and in diseases, such as rheumatoid arthritis and atherosclerosis. Stimuli, such as thrombin, histamine, and tumor necrosis factor (TNF), are powerful inducers of EC permeability, 1 whereas the angiogenic factor angiopoietin-1 (Ang-1), acting through the tyrosine kinase receptor Tie2, and sphingosine-1-phosphate (S1P), acting through the G protein coupled receptors S1P 1 or S1P 3 , inhibit the action of these stimulators and are potent protectors of barrier function. [2][3][4] The Ang-1/Tie2 axis is essential for vascular development and, in the adult, for the formation and maintenance of EC integrity. 2 In vivo, transgenic expression of Ang-1 in mice results in leakage resistant blood vessels, 5 and systemic administration of Ang-1 inhibits vessel leak. 6 In vitro, the antipermeability and antiinflammatory effects of Ang-1 appear to function at 2 levels, one to inhibit the basal permeability of EC and the other to limit the activity of agents, such as thrombin and TNF. 3 The signaling pathways regulated in response to ligand-induced phosphorylation of Tie2 are only now being elucidated. 7 AKT is involved in the prosurvival and angiogenic activities of Ang-1. 8 Interaction of ShcA with Tie2 and phospholipase D-dependent regulation of mitogen-activated protein kinase (MAPK) are involved in Ang-1-mediated cell migration 9 and a Ras/MAPK cascade is responsible for Ang-1-induced ce...

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Section: Introductionmentioning

confidence: 99%

Basal and angiopoietin-1–mediated endothelial permeability is regulated by sphingosine kinase-1

Stanković

Bonder

et al. 2008

Blood

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“…Ang1 has also been reported to induce specific effects, such as chemotactic responses through ShcA (22) and sprouting through either Dok-R or Akt activation (23). In addition, Ang1 has been demonstrated to be a potent survival factor against apoptosis induced by serum starvation (24), irradiation, and mannitol (25) through the activation of Akt in a PI 3-kinase-dependent manner.…”

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confidence: 99%

Angiopoietin-1 Attenuates H2O2-induced SEK1/JNK Phosphorylation through the Phosphatidylinositol 3-Kinase/Akt Pathway in Vascular Endothelial Cells

Murakami

Takagi

Suzuma

et al. 2005

Journal of Biological Chemistry

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“…To investigate the physiological function of Tyr 1100 in Tie2 signaling, gene targeting was performed to introduce a tyrosine to phenylalanine mutation at position 1100 (Y1100F) into the tie2 locus. The Y1100F mutation prevents the binding and/or activation of the p85 subunit of PI3-kinase, Grb7 and ShcA, but preserves the ability to phosphorylate Dok-R (2,17,19). The targeting vectors contained either the wild-type or Y1100F Tie2 cDNA followed by a simian virus 40 poly(A) sequence, a neomycin resistance gene (neo) flanked by loxP sites, and a thymidine kinase gene (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Tyrosine residue 1100 (Tyr 1100 ) appears to be a major autophosphorylation site on Tie2; binding of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-kinase) to this site results in the activation of PI3-kinase, which in turn regulates endothelial cell survival and motility (11,19,22,34). More recently, the ShcA adaptor protein was also shown to bind to this site via its SH2 domain, and the recruitment of ShcA to Tie2 was shown to affect endothelial cell migration and sprouting but not cell survival (2). An additional autophosphorylation site on Tie2, tyrosine residue 1106 (Tyr 1106 ), mediates binding to the phosphotyrosine binding domain of docking protein Dok-R, which in turn becomes tyrosine phosphorylated to allow the assembly of a signaling complex with RasGAP and Nck/Pak; the latter potentiates Ang1-induced endothelial cell migration (17,29).…”

mentioning

confidence: 99%

Selective Role of a Distinct Tyrosine Residue on Tie2 in Heart Development and Early Hematopoiesis

Tachibana

Jones

Dumont

et al. 2005

Molecular and Cellular Biology

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The development of the cardiovascular system and the development of the early hematopoietic systems are closely related, and both require signaling through the Tie2 receptor tyrosine kinase. Although endothelial cells and hematopoietic cells as well as their precursors share common gene expression patterns during development, it remains completely unknown how Tie2 signaling coordinately regulates cardiovascular development and early hematopoiesis in vivo. We show here that mice with a targeted mutation in tyrosine residue 1100 in the carboxyl-terminal tail of Tie2 display defective cardiac development and impaired hematopoietic and endothelial cell development in the paraaortic splanchnopleural mesoderm similar to that seen in Tie2-null mutant mice. Surprisingly, however, unlike Tie2-null mutant mice, mice deficient in signaling through this tyrosine residue show a normal association of perivascular cells with nascent blood vessels. These studies are the first to demonstrate the physiological importance of a single tyrosine residue in Tie2, and they suggest that multiple tyrosine residues in the receptor may coordinate cardiovascular development and early hematopoietic development.

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Adaptor ShcA Protein Binds Tyrosine Kinase Tie2 Receptor and Regulates Migration and Sprouting but Not Survival of Endothelial Cells

Cited by 44 publications

References 68 publications

Basal and angiopoietin-1–mediated endothelial permeability is regulated by sphingosine kinase-1

Basal and angiopoietin-1–mediated endothelial permeability is regulated by sphingosine kinase-1

Angiopoietin-1 Attenuates H2O2-induced SEK1/JNK Phosphorylation through the Phosphatidylinositol 3-Kinase/Akt Pathway in Vascular Endothelial Cells

Selective Role of a Distinct Tyrosine Residue on Tie2 in Heart Development and Early Hematopoiesis

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