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



Schmid, Michael C ORCID: 0000-0002-3445-0013, Kang, Sang Won, Chen, Hui, Paradise, Marc, Ghebremedhin, Anghesom, Kaneda, Megan M, Chin, Shao-Ming, Do, Anh, Watterson, D Martin and Varner, Judith A
(2022) PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation. Nature Communications, 13 (1). 1768-.

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Abstract

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

Item Type: Article
Uncontrolled Keywords: Myeloid Cells, Humans, Neoplasms, Inflammation, Myosin-Light-Chain Kinase, Cell Adhesion, Molecular Weight, Class Ib Phosphatidylinositol 3-Kinase
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 16 May 2022 09:44
Last Modified: 18 Jan 2023 21:02
DOI: 10.1038/s41467-022-29471-6
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3154870