DRD4 Interacts with TGF‐β Receptors to Drive Colorectal Cancer Metastasis Independently of Dopamine Signaling Pathway

Abstract

The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β‐Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4‐promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial‐mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH‐terminal domain is identified as the key intracellular region for the pro‐metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro‐metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy.