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Structural requirements for cub domain containing protein 1 (CDCP1) and Src dependent cell transformation

Gwendlyn Kollmorgen1, Birgit Bossenmaier, Gerhard Niederfellner

  • 1Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany.

Plos One
|January 10, 2013
PubMed

Insights

Cub domain containing protein 1 (CDCP1) and Src kinase co-overexpression drives cellular transformation. Intact CDCP1 termini and specific tyrosine residues are crucial for this transformation, highlighting key structural requirements.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cub domain containing protein 1 (CDCP1) is upregulated in various cancers, including lung, colon, ovarian, and kidney tumors.
  • CDCP1 is a membrane protein interacting with Src family kinases, but its role in cellular transformation requires further elucidation.
  • Existing research lacks experimental systems to fully evaluate CDCP1's transformation-driving features.

Purpose of the Study:

  • To define the structural requirements of CDCP1 and Src in cellular transformation.
  • To investigate the specific domains and residues of CDCP1 essential for transformation.
  • To characterize the interaction between CDCP1 and Src kinase in the context of cell transformation.

Main Methods:

  • Retrovirus-mediated co-overexpression of c-Src and CDCP1 in NIH3T3 cells to induce focus formation.
  • Utilized various CDCP1 mutants to assess the impact of specific structural features on transformation capacity.
  • Employed Src mutants to investigate the role of Src kinase domains and modifications in CDCP1-dependent transformation.

Main Results:

  • Full transformation capacity of CDCP1 requires intact amino- and carboxy-termini.
  • Mutation of core intracellular tyrosine residues (Y734, Y743, Y762) abolished transformation.
  • Mutation of the palmitoylation motif (C689,690G) significantly reduced transformation, while Src SH2 domain mutation enhanced CDCP1-dependent foci.

Conclusions:

  • The focus formation assay effectively defines structural requirements for CDCP1/Src-dependent transformation.
  • Specific intracellular tyrosine residues and intact termini of CDCP1 are critical for its oncogenic function.
  • Src kinase myristoylation is necessary, but SH2 domain binding is not essential for CDCP1-mediated transformation.

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