Aberrant G protein‐coupled receptor (GPCR) signaling drives cancer initiation and progression, but the mechanism underlying dysregulated GPCR signaling is unknown and represents a major gap in knowledge. Protease‐activated receptor‐1 (PAR1) is proteolytically activated and requires lysosomal degradation for signal termination. PAR1 overexpression correlates with high tumor grade and poor prognosis in breast cancer patients. Increased PAR1 expression results from altered receptor trafficking, which causes persistent signaling and increased invasiveness. We recently discovered that loss of the tumor suppressor α‐arrestin domain‐containing protein‐3 (ARRDC3) is responsible for dysregulated PAR1 trafficking, persistent signaling and breast cancer invasion. This work establishes for the first time a link between ARRDC3 and GPCR dysfunction in cancer. However, it is not known how ARRDC3 alters the dynamics of PAR1 signaling via receptor trafficking or if other determinants are important. We found that ARRDC3 regulates PAR1‐induced non‐canonical endosomal p38α MAPK signaling, but not PAR1‐rapid initiation of Gα12/13‐RhoA signaling from the plasma membrane. Interestingly, ARRDC3 interacts with NEDD4 ubiquitin E3 ligases via C‐terminal PPXY motifs, which is required for agonist‐induced PAR1 degradation, but not essential for regulation of p38α MAPK signaling. However, deletion of the C‐terminus tail abrogated both processes, suggesting that an additional determinant within the C‐terminustail distinct from the PPxY motifs is also important for mediating ARRDC3 function. In addition, PAR1‐stimulated invasion is dependent on p38a MAPK and regulated by ARRDC3, which requires the C‐terminal domain but is only partially suppressed by ARRDC3 PPXY mutant. We further discovered a novel phosphorylated Ser/Thr cluster in the C‐terminus that is critical for ARRDC3 function including modulation of ARRDC3 homo‐oligomerization and basal conformation. Meta‐analysis of breast cancer patients indicates that ARRDC3 and genes involved in PAR1‐activated p38α MAPK are associated with poor prognosis in the aggressive subtype of breast cancer patients. Currently, we are determining the molecular mechanisms by which phospho‐Ser/Thr cluster effects ARRDC3 conformation and function. In conclusion, this work has provided critical insight that improves our understanding of ARRDC3 function in spatiotemporal regulation of GPCRs signaling in invasive breast carcinoma, which may provide new therapeutic options for treating metastatic breast cancer.Support or Funding InformationNIH/NIGMS R35 GM127121