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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Article number1768
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Funding

These studies were supported by NIH grants 5R01CA226909 J.A.V., 5R01CA167426 J.A.V., and 5R01DE027325 J.A.V. This project was partially supported by NCI P30CA23100 to the UCSD Moores Comprehensive Cancer Center for Flow Cytometry Shared Resource services.

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

Fingerprint

Dive into the research topics of 'PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation'. Together they form a unique fingerprint.

Cite this