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A cancer-associated mutation in atypical protein kinase Cι occurs in a substrate-specific recruitment motif

Mark Linch1, Marta Sanz-Garcia, Erika Soriano

  • 11Protein Phosphorylation Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.

Science Signaling
|September 19, 2013
PubMed

Insights

A novel protein interaction site on atypical protein kinase Cι (PKCι) binds specific substrates like LLGL2 and myosin X. A common cancer mutation (R471C) disrupts this site, impairing cell polarity.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Atypical protein kinase Cι (PKCι) plays roles in cell growth, polarity, and migration.
  • Increased PKCι abundance is common in various cancers.

Purpose of the Study:

  • To identify and characterize the protein interaction surface of PKCι responsible for substrate binding.
  • To investigate the functional impact of a specific PKCι mutation (R471C) found in human cancers.

Main Methods:

  • Protein interaction studies to identify binding partners of PKCι.
  • Site-directed mutagenesis to analyze the role of specific amino acids in the dibasic motif.
  • Analysis of polarized epithelial morphogenesis in 3D cyst models.

Main Results:

  • A dibasic motif (RIPR) on PKCι was identified, binding substrates like lethal giant larvae 2 (LLGL2) and myosin X.
  • Specific arginine residues (Arg471 and Arg474) within the motif are critical for binding distinct substrates.
  • The somatic mutation R471C, the most frequent PKCι mutation in cancer, disrupts substrate binding and impairs polarized epithelial morphogenesis.
  • The intact dibasic motif is essential for normal polarized epithelial development.

Conclusions:

  • The identified dibasic motif is crucial for PKCι's substrate specificity and its role in cell polarity.
  • The R471C mutation represents a change-of-function mutation that selectively disrupts PKCι's polarizing activity by affecting substrate recruitment.
  • Understanding this mechanism provides insights into cancer development and potential therapeutic targets.

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