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Differential regulation of TROP2 release by PKC isoforms through vesicles and ADAM17

Tim M Wanger1, Sharon Dewitt1, Anne Collins2

  • 1College of Biomedical and Life Sciences, Cardiff University, Dental School, Cardiff CF14 4XY, United Kingdom.

Cellular Signalling
|March 31, 2015
PubMed

Insights

Tumor protein TROP2 cleavage by ADAM17 is PKC-dependent. Alternative TROP2 cleavage by PKCζ, independent of endocytosis, may yield a novel prostate cancer biomarker.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • TROP2 is a cell surface glycoprotein implicated in cancer progression.
  • ADAM17 is a metalloproteinase involved in shedding cell surface proteins.
  • Protein kinase C (PKC) isoforms regulate various cellular processes, including protein cleavage.

Purpose of the Study:

  • To investigate the mechanisms regulating TROP2 cleavage by ADAM17.
  • To identify the role of PKC isoforms in TROP2 processing.
  • To explore the potential of TROP2 cleavage products as cancer biomarkers.

Main Methods:

  • Inhibition of ADAM17 and PKC isoforms using specific chemical inhibitors (GW64, Bim-1, Gö6979).
  • Analysis of TROP2 cleavage products and their release mechanisms (ectosomes, microvesicles).
  • Investigation of the role of endocytosis in TROP2 processing.

Main Results:

  • ADAM17-dependent TROP2 cleavage requires novel PKC activity.
  • Full-length TROP2 is released in ectosomes upon classical PKC activation.
  • PKCζ inhibition stimulates alternative TROP2 cleavage, releasing a microvesicular product dependent on endocytosis.

Conclusions:

  • TROP2 processing is regulated by distinct PKC isoforms and metalloproteinases.
  • Alternative TROP2 cleavage products released via microvesicles may serve as novel biomarkers, particularly in prostate cancer.
  • Understanding TROP2 cleavage pathways offers insights into cancer biology and potential therapeutic targets.
Keywords:
ADAM17Ectodomain sheddingMicrovesiclesPKCTROP2

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