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The unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles

Mariam H Orme1, Gianmaria Liccardi1, Nina Moderau2

  • 1Chester Beatty Laboratories, The Breast Cancer Now Toby Robins Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, 237 Fulham Road, London SW3 6JB, UK.

Nature Communications
|March 11, 2016
PubMed

Insights

Unconventional myosins like Drosophila CRINKLED (CK) regulate non-apoptotic caspase functions by acting as substrate adaptors. This mechanism, conserved in mammals with MYO7A and CASPASE-8, influences kinase signaling pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Caspases are crucial in non-apoptotic signaling pathways regulating inflammation, cell proliferation, and migration.
  • The precise mechanisms of caspase activation and substrate processing in non-apoptotic contexts remain unclear.

Purpose of the Study:

  • To investigate the role of Drosophila unconventional myosin CRINKLED (CK) in non-apoptotic caspase functions.
  • To elucidate the molecular mechanism by which CK regulates caspase activity and downstream signaling.
  • To determine if this regulatory mechanism is conserved in mammals.

Main Methods:

  • Genetic analysis in Drosophila using mutants for CRINKLED (CK) in specific tissues like the arista, border cells, and wing imaginal discs.
  • Biochemical assays to study the interaction between CK and the initiator caspase DRONC.
  • Investigating the recruitment of SHAGGY46/GSK3-β to DRONC mediated by CK.
  • Comparative studies using mammalian homologues MYO7A and CASPASE-8, and their role in RIPK1 signaling.

Main Results:

  • Loss of CK function in Drosophila disrupts DRONC-dependent patterning in various tissues.
  • CK acts as a substrate adaptor, facilitating the recruitment of SHAGGY46/GSK3-β to DRONC for localized kinase activity modulation.
  • Mammalian MYO7A interacts with CASPASE-8, impacting the RIPK1>CASPASE-8 signaling axis.
  • Unconventional myosins play a conserved role in linking caspase activity to kinase regulation.

Conclusions:

  • Unconventional myosins are key regulators of non-apoptotic caspase functions.
  • CK and MYO7A act as crucial adaptors, mediating caspase-dependent kinase signaling.
  • This conserved mechanism highlights a novel regulatory axis in cellular signaling pathways.

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