The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis.

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  • Author(s): Sweet DT;Sweet DT; Chen Z; Wiley DM; Bautch VL; Tzima E
  • Source:
    Blood [Blood] 2012 Feb 23; Vol. 119 (8), pp. 1946-55. Date of Electronic Publication: 2011 Nov 16.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
    • Publication Information:
      Publication: 2021- : [New York] : Elsevier
      Original Publication: New York, Grune & Stratton [etc.]
    • Subject Terms:
      Signal Transduction*; Extracellular Matrix/*metabolism ; Intercellular Signaling Peptides and Proteins/*metabolism ; Neovascularization, Physiologic/*physiology ; Shc Signaling Adaptor Proteins/*metabolism; Animals ; Apoptosis/drug effects ; Blotting, Western ; Cell Movement/drug effects ; Cells, Cultured ; Embryo, Nonmammalian/blood supply ; Embryo, Nonmammalian/embryology ; Female ; Fibronectins/metabolism ; Gene Knockdown Techniques ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/physiology ; Humans ; Integrins/metabolism ; Male ; Mice ; Mice, Knockout ; Neovascularization, Physiologic/drug effects ; Neovascularization, Physiologic/genetics ; Proto-Oncogene Proteins c-akt/metabolism ; Shc Signaling Adaptor Proteins/genetics ; Vascular Endothelial Growth Factor A/pharmacology ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; Zebrafish ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
    • Abstract:
      Angiogenesis requires integration of cues from growth factors, extracellular matrix (ECM) proteins, and their receptors in endothelial cells. In the present study, we show that the adaptor protein Shc is required for angiogenesis in zebrafish, mice, and cell-culture models. Shc knockdown zebrafish embryos show defects in intersegmental vessel sprouting in the trunk. Shc flox/flox; Tie2-Cre mice display reduced angiogenesis in the retinal neovascularization model and in response to VEGF in the Matrigel plug assay in vivo. Functional studies reveal a model in which Shc is required for integrin-mediated spreading and migration specifically on fibronectin, as well as endothelial cell survival in response to VEGF. Mechanistically, Shc is required for activation of the Akt pathway downstream of both integrin and VEGF signaling, as well as for integration of signals from these 2 receptors when cells are grown on fibronectin. Therefore, we have identified a unique mechanism in which signals from 2 critical angiogenic signaling axes, integrins and VEGFR-2, converge at Shc to regulate postnatal angiogenesis.
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    • Grant Information:
      P30 CA016086 United States CA NCI NIH HHS; R01 HL043174 United States HL NHLBI NIH HHS; R01 HL088632 United States HL NHLBI NIH HHS; T32 GM007092 United States GM NIGMS NIH HHS; T32 HL069768 United States HL NHLBI NIH HHS; HL088632 United States HL NHLBI NIH HHS; R01 HL43174 United States HL NHLBI NIH HHS
    • Accession Number:
      0 (Fibronectins)
      0 (Integrins)
      0 (Intercellular Signaling Peptides and Proteins)
      0 (Shc Signaling Adaptor Proteins)
      0 (Vascular Endothelial Growth Factor A)
      0 (Zebrafish Proteins)
      EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
    • Publication Date:
      Date Created: 20111119 Date Completed: 20120521 Latest Revision: 20211021
    • Publication Date:
      20250114
    • Accession Number:
      PMC3293649
    • Accession Number:
      10.1182/blood-2011-10-384560
    • Accession Number:
      22096252