TIE2 associates with caveolae and regulates caveolin-1 to promote their nuclear translocation

Mohammad B. Hossain, Rehnuma Shifat, Jingyi Li, Xuemei Luo, Kenneth R. Hess, Yisel Rivera-Molina, Francisco Puerta Martinez, Hong Jiang, Frederick F. Lang, Mien Chie Hung, Juan Fueyo, Candelaria Gomez-Manzanoa

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

DNA repair pathways are aberrant in cancer, enabling tumor cells to survive standard therapies-chemotherapy and radiotherapy. Our group previously reported that, upon irradiation, the membrane-bound tyrosine kinase receptor TIE2 translocates into the nucleus and phosphorylates histone H4 at Tyr51, recruiting ABL1 to the DNA repair complexes that participate in the nonhomologous end-joining pathway. However, no specific molecular mechanisms of TIE2 endocytosis have been reported. Here, we show that irradiation or ligand-induced TIE2 trafficking is dependent on caveolin-1, the main component of caveolae. Subcellular fractionation and confocal microscopy demonstrated TIE2/caveolin-1 complexes in the nucleus, and using inhibitor or small interfering RNAs (siRNAs) against caveolin-1 or Tie2 inhibited their trafficking. TIE2 was found in caveolae and directly phosphorylated caveolin-1 at Tyr14 in vitro and in vivo. This modification regulated the generation of TIE2/caveolin-1 complexes and was essential for TIE2/caveolin-1 nuclear translocation. Our data further demonstrate that the combination of TIE2 and caveolin-1 inhibitors resulted in significant radiosensitization of malignant glioma cells, which will guide the development of combinatorial treatment with radiotherapy for patients with glioblastoma.

Original languageEnglish (US)
Article numbere00142-17
JournalMolecular and cellular biology
Volume37
Issue number21
DOIs
StatePublished - Nov 1 2017
Externally publishedYes

Keywords

  • Brain tumor
  • Caveolin-1
  • Nuclear translocation
  • Nuclear transport
  • Radioresistance
  • Radiosensitivity
  • TIE2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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