| First Author | Schmid MC | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 1768 |
| PubMed ID | 35365657 | Mgi Jnum | J:323887 |
| Mgi Id | MGI:7263876 | Doi | 10.1038/s41467-022-29471-6 |
| Citation | Schmid MC, et al. (2022) PI3Kgamma stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation. Nat Commun 13(1):1768 |
| abstractText | 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 PI3Kgamma-mediated Rap1 activation, leading to conformational changes in integrin alpha4beta1 that promote myeloid cell extravasation and tumor inflammation Here we show that PI3Kgamma activates a high molecular weight form of myosin light chain kinase, MLCK210, that promotes myosin-dependent Rap1 GTP loading, leading to integrin alpha4beta1 activation. Genetic or pharmacological inhibition of MLCK210 suppresses integrin alpha4beta1 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. |
