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Uncoupling of protein kinase D from suppression of EGF-dependent c-Jun phosphorylation in cancer cells

Cliff Hurd1, Enrique Rozengurt

  • 1Unit of Signal Transduction and Gastrointestinal Cancer, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine and Molecular Biology Institute, University of California, Los Angeles, CA 90095-1786, USA.

Biochemical and Biophysical Research Communications
|March 21, 2003
PubMed

Insights

Protein kinase D (PKD) normally suppresses the c-Jun N-terminal kinase (JNK) pathway. However, in lung and pancreatic cancer cells, PKD failed to inhibit JNK signaling, suggesting a loss of this regulatory mechanism in cancer.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • Protein kinase D (PKD) is a known negative regulator of the c-Jun N-terminal kinase (JNK) pathway.
  • The JNK pathway plays a role in maintaining cancerous phenotypes in lung and pancreatic cancers.
  • Previous studies showed PKD could attenuate JNK-mediated c-Jun phosphorylation in HEK 293 cells.

Purpose of the Study:

  • To investigate the effect of constitutively active PKD (PKD-S744/748E) on JNK signaling in cancer cells.
  • To determine if PKD can suppress JNK activity in non-small cell lung cancer (A549) and pancreatic cancer (Panc1) cells.
  • To assess the relationship between PKD and JNK signaling in the context of cancer phenotypes.

Main Methods:

  • Stable inducible expression of a constitutively active PKD mutant (PKD-S744/748E) in A549 and Panc1 cells.
  • Stimulation with epidermal growth factor (EGF) to activate the JNK pathway.
  • Assessment of c-Jun phosphorylation at Ser 63, a JNK substrate, as a readout for JNK activity.

Main Results:

  • Induced expression of PKD-S744/748E in A549 and Panc1 cells did not attenuate EGF-stimulated c-Jun phosphorylation.
  • This indicates that JNK-mediated c-Jun phosphorylation is uncoupled from PKD suppression in these cancer cell lines.
  • The inhibitory effect of PKD on JNK signaling observed in HEK 293 cells was not replicated in cancer cells.

Conclusions:

  • PKD-mediated suppression of JNK signaling is impaired in A549 non-small cell lung cancer and Panc1 pancreatic cancer cells.
  • The uncoupling of PKD and JNK pathways in cancer cells may contribute to sustained JNK signaling and cancer progression.
  • Further research is needed to understand the mechanisms behind this pathway dissociation in cancer.

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