Abstract
G protein–coupled receptors (GPCRs) represent the largest family of surface receptors and are responsible for key physiological functions, including cell growth, neurotransmission, hormone release, and cell migration. The GPCR 56 (GPR56), encoded by ADGRG1, is an adhesion GPCR found on diverse cell types, including neural progenitor cells, melanoma cells, and lymphocytes, such as effector memory T cells, γδ T cells, and NK cells. Using RNA-sequencing and high-resolution flow cytometry, we found that GPR56 mRNA and protein expression increased with NK cell differentiation, reaching its peak in adaptive NK cells. Small interfering RNA silencing of GPR56 led to increased spontaneous and chemokine-induced migration, suggesting that GPR56 functions as an upstream checkpoint for migration of highly differentiated NK cells. Increased NK cell migration could also be induced by agonistic stimulation of GPR56 leading to rapid internalization and deactivation of the receptor. Mechanistically, GPR56 ligation and downregulation were associated with transcriptional coactivator with PDZ-binding motif translocation to the nucleus and increased actin polymerization. Together, these data provide insights into the role of GPR56 in the migratory behavior of human NK cell subsets and may open possibilities to improve NK cell infiltration into cancer tissues by releasing a migratory checkpoint.
Footnotes
This work was supported by the Research Council of Norway (Norges Forskningsråd; Projects 275469 and 237579); Research Council of Norway (Norges Forskningsråd) through its Centres of Excellence scheme (Project 332727); Norwegian Cancer Society (Kreftforeningen; Projects 190386 and 223310); Ministry of Health and Care Services, The South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF; Grant 2021-073); network grant of the European Commission (H2020-MSCA-MC-ITN-765104-MATURE-NK); Knut and Alice Wallenberg Foundation (Knut och Alice Wallenbergs Stiftelse); and Swedish Foundation for Strategic Research. R.K.M. was supported by the European Union’s Horizon 2020 research and innovation program under Marie Sklodowska-Curie Actions Grant 801133. This work was further supported by grants from the Swedish Research Council (223310), Swedish Children’s Cancer Society (PR2020-1059), Swedish Cancer Society (Cancerfonden; 21-1793Pj), Sweden’s Innovation Agency, Karolinska Institutet, and National Cancer Institute (P01 CA111412 and P009500901) (all to K.-J.M.).
The online version of this article contains supplemental material.
The sequencing data presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE245690) under accession number GSE245690.
