Anxa4, a member of the Annexin family, is a calcium ion (Ca2+)- and phospholipid-binding protein. It is involved in multiple biological processes, with its function potentially associated with various signaling pathways, such as the PI3K/Akt/eNOS pathway, JAK-STAT3 signaling, and Wnt signaling. Its abnormal expression has been linked to the development of many diseases, highlighting its biological importance [1,2,3]. Genetic models like KO/CKO mouse models can be valuable in further exploring its functions.

In preeclampsia, Anxa4 expression was downregulated in human placentas and placenta-derived extravillous cytotrophoblasts. Overexpression of Anxa4 in human trophoblast cells promoted cell proliferation and invasion, inhibited apoptosis, and upregulated proteins in the PI3K/Akt/eNOS pathway, while knockdown had opposite effects. Inhibition of the PI3K/Akt pathway abrogated Anxa4-overexpression-mediated effects. In an l-NAME-induced PE rat model, Anxa4 overexpression alleviated PE progression [1]. In basal-like breast cancer, Anxa4 was upregulated, and high-expression patients had worse survival. Anxa4 could positively modulate cyclin D1 expression and G1/S progression, and activate JAK-STAT3 signaling by interacting with ANXA1 [2]. In high-glucose-induced fibroblast migration, the GSK3β-Ikaros-ANXA4 signaling pathway inhibited fibroblast cell migration. Suppression of ANXA4 promoted cell migration [3].

In conclusion, Anxa4 plays crucial roles in various biological processes and disease conditions. Model-based research, especially studies using KO/CKO mouse models if available in the future, could further clarify its functions. In preeclampsia, Anxa4 may promote trophoblast invasion via the PI3K/Akt/eNOS pathway. In basal-like breast cancer, it activates JAK-STAT3 signaling, and in high-glucose-induced fibroblast migration, it is part of a signaling pathway that inhibits migration. These findings enhance our understanding of Anxa4's functions and its potential as a therapeutic target in related diseases.

References:

1. Xu, Yalan, Sui, Lili, Qiu, Bintao, Liu, Juntao, Zhang, Xiaohong. 2019. ANXA4 promotes trophoblast invasion via the PI3K/Akt/eNOS pathway in preeclampsia. In American journal of physiology. Cell physiology, 316, C481-C491. doi:10.1152/ajpcell.00404.2018. https://pubmed.ncbi.nlm.nih.gov/30673304/

2. Li, Lei, Zhang, Rong, Liu, Ying, Zhang, Gong. 2020. ANXA4 Activates JAK-STAT3 Signaling by Interacting with ANXA1 in Basal-Like Breast Cancer. In DNA and cell biology, 39, 1649-1656. doi:10.1089/dna.2020.5570. https://pubmed.ncbi.nlm.nih.gov/32552056/

3. Wang, Youpei, Zheng, Xiang, Wang, Qing, Zheng, Meiqin, Pang, Lingxia. 2020. GSK3β-Ikaros-ANXA4 signaling inhibits high-glucose-induced fibroblast migration. In Biochemical and biophysical research communications, 531, 543-551. doi:10.1016/j.bbrc.2020.07.142. https://pubmed.ncbi.nlm.nih.gov/32807499/