RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma

Cell Death Dis. 2016 Dec 29;7(12):e2572. doi: 10.1038/cddis.2016.436.


Suppression of anoikis is a prerequisite for tumor cell metastasis, which is correlated with chemoresistance and poor prognosis. We characterized a novel interaction between RanBP9 SPRY domain and TSSC3 PH domain by which RanBP9/TSSC3 complex exerts transcription and post-translation regulation in osteosarcoma. RanBP9/TSSC3 complex was inversely correlated with a highly anoikis-resistant phenotype in osteosarcoma cells and metastasis in human osteosarcoma. RanBP9 cooperated with TSSC3 to inhibit anchorage-independent growth and to promote anoikis in vitro and suppress lung metastasis in vivo. Moreover, RanBP9 SPRY domain was required for RanBP9/TSSC3 complex-mediated anoikis resistance. Mechanistically, RanBP9 formed a ternary complex with TSSC3 and Src to scaffold this interaction, which suppressed both Src and Src-dependent Akt pathway activations and facilitated mitochondrial-associated anoikis. Collectively, the newly identified RanBP9/TSSC3 complex cooperatively suppress metastasis via downregulation of Src-dependent Akt pathway to expedite mitochondrial-associated anoikis. This study provides a biological basis for exploring the therapeutic significance of dual targeting of RanBP9 and TSSC3 in osteosarcoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adolescent
  • Adult
  • Animals
  • Anoikis*
  • Cell Line, Tumor
  • Cell Proliferation
  • Child
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / metabolism*
  • Down-Regulation
  • Female
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Male
  • Mice, SCID
  • Mitochondria / metabolism
  • Models, Biological
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Osteosarcoma / enzymology
  • Osteosarcoma / pathology*
  • Phenotype
  • Protein Binding
  • Protein Domains
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction*
  • Transcription, Genetic
  • Young Adult
  • src-Family Kinases / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Nuclear Proteins
  • Ran binding protein 9
  • TSSC3 protein
  • src-Family Kinases
  • Proto-Oncogene Proteins c-akt