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PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation

Author

Listed:
  • Michael C. Schmid

    (University of California, San Diego)

  • Sang Won Kang

    (Ewha Womans University)

  • Hui Chen

    (University of California, San Diego)

  • Marc Paradise

    (University of California, San Diego)

  • Anghesom Ghebremedhin

    (University of California, San Diego)

  • Megan M. Kaneda

    (University of California, San Diego)

  • Shao-Ming Chin

    (University of California, San Diego)

  • Anh Do

    (University of California, San Diego)

  • D. Martin Watterson

    (Northwestern University)

  • Judith A. Varner

    (University of California, San Diego
    University of California, San Diego)

Abstract

Myeloid cells play key roles in cancer immune suppression and tumor progression. In response to tumor derived factors, circulating monocytes and granulocytes extravasate into the tumor parenchyma where they stimulate angiogenesis, immune suppression and tumor progression. Chemokines, cytokines and interleukins stimulate PI3Kγ-mediated Rap1 activation, leading to conformational changes in integrin α4β1 that promote myeloid cell extravasation and tumor inflammation Here we show that PI3Kγ activates a high molecular weight form of myosin light chain kinase, MLCK210, that promotes myosin-dependent Rap1 GTP loading, leading to integrin α4β1 activation. Genetic or pharmacological inhibition of MLCK210 suppresses integrin α4β1 activation, as well as tumor inflammation and progression. These results demonstrate a critical role for myeloid cell MLCK210 in tumor inflammation and serve as basis for the development of alternative approaches to develop immune oncology therapeutics.

Suggested Citation

  • Michael C. Schmid & Sang Won Kang & Hui Chen & Marc Paradise & Anghesom Ghebremedhin & Megan M. Kaneda & Shao-Ming Chin & Anh Do & D. Martin Watterson & Judith A. Varner, 2022. "PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29471-6
    DOI: 10.1038/s41467-022-29471-6
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    References listed on IDEAS

    as
    1. Michael C. Schmid & Samia Q. Khan & Megan M. Kaneda & Paulina Pathria & Ryan Shepard & Tiani L. Louis & Sudarshan Anand & Gyunghwi Woo & Chris Leem & M. Hafeez Faridi & Terese Geraghty & Anugraha Raja, 2018. "Integrin CD11b activation drives anti-tumor innate immunity," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Megan M. Kaneda & Karen S. Messer & Natacha Ralainirina & Hongying Li & Christopher J. Leem & Sara Gorjestani & Gyunghwi Woo & Abraham V. Nguyen & Camila C. Figueiredo & Philippe Foubert & Michael C. , 2016. "PI3Kγ is a molecular switch that controls immune suppression," Nature, Nature, vol. 539(7629), pages 437-442, November.
    Full references (including those not matched with items on IDEAS)

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