Ckap4, also known as Cytoskeleton Associated Protein 4, is an endoplasmic reticulum protein present in the cell surface membrane. It acts as a receptor for proteins like Dickkopf-1 (DKK1), Dickkopf-3 (DKK3), and is involved in multiple signaling pathways. It plays a role in regulating cell migration through its interaction with and control of integrin recycling [4]. It is also associated with processes like reticulophagy regulation [2], and is important in various biological contexts, with its study in genetic models providing insights into its functions.

In glioblastoma, knockdown of Ckap4 reduced the malignant potential of cells, while overexpression increased Forkhead Box M1 (FOXM1) expression along with elevated AKT and ERK phosphorylation [1]. In hepatocellular carcinoma, Ckap4 competitively binds to RETREG1, protecting it from degradation, and is involved in regulating reticulophagy and cancer progression [2]. In lung cancer, Ckap4 is secreted with exosomes, and its overexpression promotes cell proliferation, making it a potential biomarker and therapeutic target [3]. In oral cancer, the DKK3/Ckap4 axis is associated with advanced stage and poorer prognosis, and anti-Ckap4 antibodies can suppress cancer cell activities [5]. In atrial fibroblasts, Ckap4 is involved in tryptase-induced phenotypic conversion through the PAR2/p38/JNK pathway [6]. In chronic kidney disease, Ckap4 contributes to vascular calcification by modulating YAP phosphorylation and MMP2 expression [7].

In conclusion, Ckap4 is a multifunctional protein involved in regulating cell migration, reticulophagy, and is crucial in the progression of various cancers such as glioblastoma, hepatocellular carcinoma, lung cancer, and oral cancer. It also plays a role in atrial fibrosis and the progression of vascular calcification in chronic kidney disease. The study of Ckap4 using gene knockout or conditional knockout mouse models has significantly contributed to understanding its functions in these disease conditions, providing potential therapeutic targets for 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. 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/

4. 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/

5. 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/

6. 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/

7. 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/