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PKCdelta plays opposite roles in growth mediated by wild-type Kit and an oncogenic Kit mutant

Tanya Jelacic1, Diana Linnekin

  • 1Basic Research Laboratory, Center for Cancer Research, Bldg 469, Rm 205, National Cancer Institute-Frederick, Frederick, MD 21702, USA. t_jelacic_obreiter@ncifcrf.gov

Blood
|November 16, 2004
PubMed

Insights

Protein kinase Cdelta (PKCdelta) plays a dual role in Kit receptor signaling. It promotes growth of oncogenic Kit mutants but inhibits normal Kit receptor-mediated cell growth.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • The Kit receptor tyrosine kinase is essential for normal hematopoiesis.
  • Mutations in c-kit, such as the D814Y oncogenic form, lead to dysregulated cell growth.
  • The role of protein kinase Cdelta (PKCdelta) in Kit signaling pathways is not fully understood.

Purpose of the Study:

  • To investigate the function of PKCdelta in cellular responses mediated by both wild-type (WT) Kit and the oncogenic D814Y Kit mutant.
  • To elucidate the differential roles of PKCdelta in normal versus oncogenic Kit signaling.

Main Methods:

  • Utilized a murine mast cell-like cell line expressing WT Kit or the D814Y Kit mutant.
  • Investigated PKCdelta activation status and its interaction with Kit.
  • Employed pharmacological inhibitors (rottlerin) and dominant-negative constructs to modulate PKCdelta activity.
  • Assessed the effects of PKCdelta modulation on cell growth.

Main Results:

  • PKCdelta is activated by stem cell factor (SCF) binding to WT Kit and is constitutively active in cells with the D814Y Kit mutant.
  • PKCdelta physically interacts with both WT and mutant Kit.
  • Inhibition of PKCdelta suppressed the growth of cells expressing the D814Y mutant Kit.
  • Conversely, SCF-induced growth of WT Kit-expressing cells was not inhibited by PKCdelta inhibition.
  • Overexpression of PKCdelta inhibited WT Kit cell growth but enhanced D814Y mutant Kit cell growth.

Conclusions:

  • PKCdelta promotes factor-independent growth of cells harboring the oncogenic D814Y Kit mutation.
  • PKCdelta negatively regulates SCF-induced growth in cells with wild-type Kit.
  • This study demonstrates distinct functions for PKCdelta in the context of normal versus oncogenic Kit receptor signaling, highlighting its complex role in cell proliferation.

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