Gga3, also known as Golgi-associated, γ adaptin ear containing, ADP-ribosylation factor-binding protein 3, is involved in multiple cellular processes. It plays a role in the recycling and signaling of G protein-coupled receptors (GPCRs), such as the PGD2 receptor DP1 [2], and is also associated with the anterograde trafficking of nascent GPCRs like α2-adrenergic receptors [4]. Additionally, it is involved in the endocytic recycling of receptor tyrosine kinases, including RET51 [3] and TrkA [6], which impacts cell migration, invasion, and survival.

In gene-deleted C57BL/6J mice, Gga3 deletion leads to elevated fasting blood glucose levels [1]. In the context of Alzheimer's disease, Gga3 deletion or a rare variant associated with late-onset Alzheimer's disease disrupts the axonal trafficking of BACE1, causing its accumulation in axonal swellings, and exacerbates axonal dystrophies in an AD mouse model before β-amyloid deposition [5].

In conclusion, Gga3 is crucial for processes like receptor recycling and trafficking, which are essential for normal cellular function. Studies using Gga3-deleted mouse models have revealed its significance in glucose metabolism and Alzheimer's disease pathogenesis, providing valuable insights into the role of Gga3 in these biological processes and disease conditions.

References:

1. Zhang, Xiaohong, Yue, Song, Jiang, Dongjun, Liu, Jianli, Li, Xuezhi. 2023. Gga3 gene-deleted C57BL/6J mice have elevated fasting blood glucose levels. In Genes & diseases, 10, 2206-2209. doi:10.1016/j.gendis.2023.02.031. https://pubmed.ncbi.nlm.nih.gov/37554210/

2. Fréchette, Louis, Binda, Chantal, Génier, Samuel, Boisvert, Marilou, Parent, Jean-Luc. 2020. GGA3 interacts with L-type prostaglandin D synthase and regulates the recycling and signaling of the DP1 receptor for prostaglandin D2 in a Rab4-dependent mechanism. In Cellular signalling, 72, 109641. doi:10.1016/j.cellsig.2020.109641. https://pubmed.ncbi.nlm.nih.gov/32334026/

3. Crupi, Mathieu J F, Maritan, Sarah M, Reyes-Alvarez, Eduardo, Antonescu, Costin N, Mulligan, Lois M. 2019. GGA3-mediated recycling of the RET receptor tyrosine kinase contributes to cell migration and invasion. In Oncogene, 39, 1361-1377. doi:10.1038/s41388-019-1068-z. https://pubmed.ncbi.nlm.nih.gov/31645646/

4. Zhang, Maoxiang, Davis, Jason E, Li, Chunman, Terry, Alvin V, Wu, Guangyu. 2016. GGA3 Interacts with a G Protein-Coupled Receptor and Modulates Its Cell Surface Export. In Molecular and cellular biology, 36, 1152-63. doi:10.1128/MCB.00009-16. https://pubmed.ncbi.nlm.nih.gov/26811329/

5. Lomoio, Selene, Willen, Rachel, Kim, WonHee, Tanzi, Rudolph E, Tesco, Giuseppina. . Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer's disease trigger BACE1 accumulation in axonal swellings. In Science translational medicine, 12, . doi:10.1126/scitranslmed.aba1871. https://pubmed.ncbi.nlm.nih.gov/33208500/

6. Li, Xuezhi, Lavigne, Pierre, Lavoie, Christine. 2015. GGA3 mediates TrkA endocytic recycling to promote sustained Akt phosphorylation and cell survival. In Molecular biology of the cell, 26, 4412-26. doi:10.1091/mbc.E15-02-0087. https://pubmed.ncbi.nlm.nih.gov/26446845/