GIPC3, short for GAIP interacting protein c terminus 3, encodes a 312-amino-acid protein and belongs to a small family of proteins characterized by a centrally located PDZ domain [1]. It has been implicated in multiple biological processes. In the auditory system, it is essential for normal hearing as its variants are associated with non-syndromic hearing loss [1]. It may also be involved in pathways related to cancer pathogenesis, as it positively modulates Hedgehog signaling and melanoma growth [4].

In Gipc3KO/KO mice, early postnatal mechanotransduction currents were mostly normal, but by 1 month of age, there was no auditory brainstem response. The cuticular plates of hair cells in these KO mice did not flatten as in controls, and hair bundles were squeezed along the cochlear axis. Junctions between inner hair cells and adjacent inner phalangeal cells were severely disrupted. GIPC3 binds directly to MYO6, and loss of MYO6 leads to altered GIPC3 distribution. It also interacts with proteins containing PDZ-binding motifs, suggesting it couples to cytoskeletal and cell-junction proteins to shape the cuticular plate [2,3]. In addition, in mouse embryonic stem cells, GIPC3 was identified as a BRCA2 genetic interactor contributing to the survival of Brca2-null cells [5].

In conclusion, GIPC3 plays a crucial role in the auditory system, influencing the structure and function of cochlear hair cells. Its function in shaping the hair cell's cuticular plate and stereocilia arrangement is evident from studies on Gipc3-deficient mice. Additionally, its role in cancer-related pathways and as a BRCA2 genetic interactor shows its significance in multiple biological contexts and disease areas.

References:

1. Li, Xinxin, Shi, Lin, Wang, Liang. 2023. A review of the mechanisms underlying the role of the GIPC3 gene in hereditary deafness. In Frontiers in synaptic neuroscience, 14, 1101587. doi:10.3389/fnsyn.2022.1101587. https://pubmed.ncbi.nlm.nih.gov/36704659/

2. Chatterjee, Paroma, Morgan, Clive P, Krey, Jocelyn F, Ricci, Anthony J, Barr-Gillespie, Peter G. 2023. GIPC3 couples to MYO6 and PDZ domain proteins, and shapes the hair cell apical region. In Journal of cell science, 136, . doi:10.1242/jcs.261100. https://pubmed.ncbi.nlm.nih.gov/37096733/

3. Chatterjee, Paroma, Morgan, Clive P, Krey, Jocelyn F, Ricci, Anthony J, Barr-Gillespie, Peter G. 2023. GIPC3 couples to MYO6 and PDZ domain proteins and shapes the hair cell apical region. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.02.28.530466. https://pubmed.ncbi.nlm.nih.gov/36909580/

4. Patmanathan, Sathya Narayanan, Tong, Bing Teck, Teo, Jia Hao Jackie, Ta, Yng-Cun, Woo, Wei-Meng. 2021. A PDZ Protein GIPC3 Positively Modulates Hedgehog Signaling and Melanoma Growth. In The Journal of investigative dermatology, 142, 179-188.e4. doi:10.1016/j.jid.2021.04.033. https://pubmed.ncbi.nlm.nih.gov/34224745/

5. Ding, Xia, Philip, Subha, Martin, Betty K, Ji, Xinhua, Sharan, Shyam K. 2017. Survival of BRCA2-Deficient Cells Is Promoted by GIPC3, a Novel Genetic Interactor of BRCA2. In Genetics, 207, 1335-1345. doi:10.1534/genetics.117.300357. https://pubmed.ncbi.nlm.nih.gov/29021281/