CKAP4, also known as Cytoskeleton Associated Protein 4, is an endoplasmic reticulum protein that also exists on the cell surface membrane. It acts as a receptor for proteins like Dickkopf-1 (DKK1), Dickkopf-3 (DKK3), and is involved in multiple pathways such as the phosphorylation of AKT, ERK, and the regulation of integrin recycling. It plays a crucial role in various biological processes including cell adhesion, migration, and mitochondrial functions, and is associated with diseases like cancer, kidney disease, and atrial fibrosis [1-7, 9]. Genetic models, especially gene knockout models, are valuable for studying CKAP4's functions.

In glioblastoma cells, CKAP4 knockdown reduced their malignant potential, while overexpression increased the expression of FOXM1 and phosphorylation levels of AKT and ERK, revealing a CKAP4-FOXM1 signaling cascade regulating glioblastoma malignancy [1]. In hepatocellular carcinoma, CKAP4 competitively binds to RETREG1, shielding it from proteasomal degradation, and thus regulating reticulophagy and cancer progression [2]. Deletion of either DKK1 or CKAP4 inhibited HCC cell growth, indicating the importance of the DKK1-CKAP4 axis in HCC aggressiveness [3]. In lung cancer, CKAP4 overexpression promoted cell proliferation, and an anti-CKAP4 antibody could inhibit this, suggesting it as a potential biomarker and therapeutic target [4]. Knockdown of CKAP4 in S2-CP8 cells enlarged cell adhesion sites, enhanced cell adhesion, and decreased cell migration by regulating α5β1 integrin recycling [5]. In oral cancer, anti-CKAP4 antibody suppressed cancer cell proliferation, migration, and invasion, with DKK3/CKAP4 axis being associated with advanced stage and poorer prognosis [6]. In atrial fibroblasts, CKAP4 participated in tryptase-induced phenotypic conversion through the PAR2/p38/JNK pathway [7]. In HeLaS3 cells, CKAP4 knockout altered mitochondrial structures and functions [8]. In chronic kidney disease, silencing CKAP4 reduced vascular smooth muscle cell calcification and expression of YAP and MMP2 [9].

In conclusion, CKAP4 plays essential roles in multiple biological processes and is closely associated with various diseases. Gene knockout models have significantly contributed to understanding its functions in cancer, kidney disease, and other disease areas, providing potential targets for disease treatment.

References:

1. Xu, Kaiyue, Zhang, Kaiqian, Ma, Jiying, Wang, Liang, Wang, Huijuan. 2023. CKAP4-mediated activation of FOXM1 via phosphorylation pathways regulates malignant behavior of glioblastoma cells. In Translational oncology, 29, 101628. doi:10.1016/j.tranon.2023.101628. https://pubmed.ncbi.nlm.nih.gov/36701930/

2. Mo, Jie, Su, Chen, Li, Pengcheng, Chen, Jin, Zhang, Bixiang. 2024. CKAP4 in hepatocellular carcinoma: competitive RETREG1/FAM134B binding, reticulophagy regulation, and cancer progression. In Autophagy, 21, 840-859. doi:10.1080/15548627.2024.2435236. https://pubmed.ncbi.nlm.nih.gov/39689859/

3. Iguchi, Kosuke, Sada, Ryota, Matsumoto, Shinji, Fukumoto, Takumi, Kikuchi, Akira. 2023. DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness. In Cancer science, 114, 2063-2077. doi:10.1111/cas.15743. https://pubmed.ncbi.nlm.nih.gov/36718957/

4. Nagoya, Akihiro, Sada, Ryota, Kimura, Hirokazu, Shintani, Yasushi, Kikuchi, Akira. 2023. CKAP4 is a potential exosomal biomarker and therapeutic target for lung cancer. In Translational lung cancer research, 12, 408-426. doi:10.21037/tlcr-22-571. https://pubmed.ncbi.nlm.nih.gov/37057110/

5. Osugi, Yoshihito, Fumoto, Katsumi, Kikuchi, Akira. 2019. CKAP4 Regulates Cell Migration via the Interaction with and Recycling of Integrin. In Molecular and cellular biology, 39, . doi:10.1128/MCB.00073-19. https://pubmed.ncbi.nlm.nih.gov/31160493/

6. Katase, Naoki, Kudo, Kodai, Ogawa, Kazuhiro, Yamauchi, Akira, Fujita, Shuichi. 2022. DKK3/CKAP4 axis is associated with advanced stage and poorer prognosis in oral cancer. In Oral diseases, 29, 3193-3204. doi:10.1111/odi.14277. https://pubmed.ncbi.nlm.nih.gov/35708905/

7. Tan, Hongwei, Chen, Zhisong, Chen, Fei, Xu, Wenjun, Liu, Xuebo. 2021. CKAP4 participates in tryptase-induced phenotypic conversion in atrial fibroblasts through PAR2/p38/JNK pathway. In American journal of translational research, 13, 2270-2282. doi:. https://pubmed.ncbi.nlm.nih.gov/34017388/

8. Harada, Takeshi, Sada, Ryota, Osugi, Yoshito, Harada, Akihiro, Kikuchi, Akira. 2020. Palmitoylated CKAP4 regulates mitochondrial functions through an interaction with VDAC2 at ER-mitochondria contact sites. In Journal of cell science, 133, . doi:10.1242/jcs.249045. https://pubmed.ncbi.nlm.nih.gov/33067255/

9. Shi, Yuping, Jin, Xiucai, Yang, Man, Wang, Kui, Rong, Shu. 2022. CKAP4 contributes to the progression of vascular calcification (VC) in chronic kidney disease (CKD) by modulating YAP phosphorylation and MMP2 expression. In Cellular signalling, 93, 110270. doi:10.1016/j.cellsig.2022.110270. https://pubmed.ncbi.nlm.nih.gov/35108641/