The Rab18/Ras/ERK/FosB/MMP3 Signaling Pathway Mediates Cell Migration Regulation by 2′3′-cGAMP

• Published in: International journal of molecular sciences Vol. 26; no. 12; p. 5758
• Main Authors: Deng, Yu, Yuan, Runjie, Liu, Pengda
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 16.06.2025; MDPI
• Subjects: Cancer therapies; Cell adhesion & migration; Cell growth; Immunity (Disease); Kinases; Phosphorylation; Proteins; Signal transduction; North Carolina; United States; Massachusetts
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms26125758

The unique secondary messenger 2′3′-cGAMP, produced by cGAS in response to cytosolic dsDNA, plays a critical role in activating innate immunity by binding to and activating STING via cell-intrinsic, autocrine, or paracrine mechanisms. Recently, we identified Rab18 as a novel, STING-independent binder of 2′3′-cGAMP. Binding of 2′3′-cGAMP to Rab18 promotes Rab18 activation and induces cell migration. However, the downstream mechanisms by which 2′3′-cGAMP-induced Rab18 activation regulates cell migration remain largely unclear. Herein, using phospho-profiling analysis, we identify MAPK signaling as a key downstream effector of the 2′3′-cGAMP/Rab18 axis that promotes the expression of FosB2 and drives cell migration. Furthermore, we identify MMP3 as a major transcriptional target of FosB2, through which the 2′3′-cGAMP/Rab18/MAPK/FosB2 signaling pathway positively regulates cell migration. Together, our findings provide new mechanistic insights into how 2′3′-cGAMP signaling controls cell migration and suggest the potential of MAPK inhibitors to block 2′3′-cGAMP-induced migratory responses.