# CKAP4

## Overview
CKAP4, or cytoskeleton-associated protein 4, is a gene that encodes a type II transmembrane protein involved in various cellular processes. The CKAP4 protein is characterized by its single transmembrane domain and is primarily localized to the endoplasmic reticulum (ER), where it plays a critical role in anchoring the ER to microtubules, thereby stabilizing cellular structures (Tuffy2012CytoskeletonAssociated; Zacharias2012Antiproliferative). Additionally, CKAP4 functions as a receptor for several ligands, including antiproliferative factor (APF) and surfactant protein A (SP-A), influencing cellular proliferation and surfactant uptake, respectively (Zacharias2012Antiproliferative). The protein's activity is modulated by post-translational modifications such as palmitoylation and phosphorylation, which affect its localization and function (Harada2020Palmitoylated; Zacharias2012Antiproliferative). CKAP4 is also implicated in various cancers, where its expression levels can serve as a prognostic marker, highlighting its potential as a therapeutic target (Cai2023Expression; Li2021CytoskeletonAssociated).

## Structure
CKAP4, also known as cytoskeleton-associated protein 4, is a type II transmembrane protein characterized by a single transmembrane domain. It consists of a 106-amino acid cytosolic tail, a 21-amino acid transmembrane domain, and a large extracellular domain comprising 474 amino acids (Chavda2017Antiproliferative). The extracellular domain includes coiled-coil domains and a predicted leucine zipper, which are structural motifs that facilitate protein-protein interactions (Chavda2017Antiproliferative). This domain is rich in positively charged, basic amino acids and is amphipathic, suggesting its potential for intermolecular interactions (Chavda2017Antiproliferative).

CKAP4 undergoes post-translational modifications, including palmitoylation at cysteine 100, which is crucial for its localization to lipid rafts in the plasma membrane and its interaction with other proteins such as VDAC2 (Harada2020Palmitoylated). This palmitoylation is catalyzed by ZDHHC2 and ZDHHC5 (Harada2020Palmitoylated). CKAP4 is also known to be reversibly palmitoylated, which affects its cellular localization and function (Kimura2016CKAP4). The protein may exist in different isoforms due to alternative splicing, although specific isoforms are not detailed in the provided context.

## Function
CKAP4, or cytoskeleton-associated protein 4, is a type II transmembrane protein that plays a crucial role in maintaining cellular structure and function. In healthy human cells, CKAP4 is primarily localized to the endoplasmic reticulum (ER), where it anchors the rough ER to microtubules, stabilizing both the ER and the microtubule network (Tuffy2012CytoskeletonAssociated; Zacharias2012Antiproliferative). This interaction is regulated by the phosphorylation of serine residues in its N-terminal domain, which affects its binding to microtubules (Zacharias2012Antiproliferative).

CKAP4 also functions as a receptor on the plasma membrane for various ligands, including antiproliferative factor (APF), surfactant protein A (SP-A), and tissue plasminogen activator (tPA). These interactions are involved in processes such as APF-mediated signaling, which influences cellular proliferation and gene expression, and SP-A-induced surfactant uptake in the lungs, contributing to lung lipid homeostasis (Tuffy2012CytoskeletonAssociated; Zacharias2012Antiproliferative).

CKAP4's role extends to the nucleus, where it can translocate in response to APF treatment, potentially influencing transcription by binding to genomic DNA. This nuclear translocation is dependent on post-translational modifications like phosphorylation and palmitoylation (Zacharias2012Antiproliferative). These diverse functions highlight CKAP4's involvement in critical cellular processes, including maintaining ER structure, regulating gene expression, and mediating cellular responses to external signals.

## Clinical Significance
CKAP4, also known as cytoskeleton-associated protein 4, is implicated in various cancers and other diseases due to alterations in its expression or interactions. In nasopharyngeal carcinoma (NPC), high CKAP4 expression is associated with poor prognosis, increased metastasis, and lower overall survival rates. It is upregulated in metastatic tissues and linked to epithelial-mesenchymal transition (EMT), influencing tumor invasiveness (Cai2023Expression). In pancreatic ductal adenocarcinoma (PDAC), CKAP4 is overexpressed and correlates with poor survival outcomes. It is secreted in exosomes, making it a potential biomarker for diagnosis and therapy (Kimura2019CKAP4; Li2021CytoskeletonAssociated).

CKAP4 also plays a role in lung cancer, where it acts as an oncogene, promoting tumor proliferation through the PI3K/AKT pathway. Its expression is linked to shorter relapse-free survival (Li2021CytoskeletonAssociated). In hepatocellular carcinoma (HCC), CKAP4 expression is associated with better outcomes, acting as an inhibitor of cell growth and metastasis (Li2021CytoskeletonAssociated). In cholangiocarcinoma, CKAP4 is a key oncogenic mediator, with high expression levels predicting poorer prognosis (Wang2021Plasmalemma). These findings highlight CKAP4's potential as a biomarker and therapeutic target across various cancer types.

## Interactions
CKAP4, or cytoskeleton-associated protein 4, is involved in various interactions with proteins and nucleic acids, playing a significant role in cellular processes. CKAP4 interacts with VDAC2 at ER-mitochondria contact sites, a process crucial for maintaining mitochondrial structure and function. This interaction is dependent on the palmitoylation of CKAP4, specifically at amino acid residues 100-106, and is facilitated by the palmitoyl acyltransferase ZDHHC2 (Harada2020Palmitoylated).

CKAP4 also interacts with the long non-coding RNA SENCR, which stabilizes vascular endothelial cell adherens junctions. This interaction occurs through a noncanonical RNA-binding domain within CKAP4, affecting the localization and function of CDH5, a key component of adherens junctions (Lyu2018SENCRstabilizes).

CKAP4 serves as a receptor for various extracellular ligands, including Dickkopf1 (DKK1), surfactant protein A (SP-A), and antiproliferative factor (APF). These interactions influence processes such as Wnt signaling, surfactant turnover, and cell proliferation (Li2021CytoskeletonAssociated).

In cardiac tissues, CKAP4 acts as an RNA-binding protein, interacting with non-coding RNAs and influencing gene expression related to cardiac remodeling (Zhu2021RNABinding).


## References


[1. (Tuffy2012CytoskeletonAssociated) Kevin M. Tuffy and Sonia Lobo Planey. Cytoskeleton-associated protein 4: functions beyond the endoplasmic reticulum in physiology and disease. ISRN Cell Biology, 2012:1–11, October 2012. URL: http://dx.doi.org/10.5402/2012/142313, doi:10.5402/2012/142313. This article has 8 citations.](https://doi.org/10.5402/2012/142313)

[2. (Cai2023Expression) Manbo Cai, Weijun Wu, Shengling Deng, Qiao Yang, Haibiao Wu, Haiyun Wang, Jiaxing Zhang, Qisheng Feng, Jianyong Shao, Yixin Zeng, and Jianjun Li. Expression of cytoskeleton-associated protein 4 is associated with poor prognosis and metastasis in nasopharyngeal carcinoma. Experimental Biology and Medicine, 248(12):1085–1094, May 2023. URL: http://dx.doi.org/10.1177/15353702231167940, doi:10.1177/15353702231167940. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1177/15353702231167940)

[3. (Chavda2017Antiproliferative) Burzin Chavda, Jun Ling, Thomas Majernick, and Sonia Lobo Planey. Antiproliferative factor (apf) binds specifically to sites within the cytoskeleton-associated protein 4 (ckap4) extracellular domain. BMC Biochemistry, September 2017. URL: http://dx.doi.org/10.1186/s12858-017-0088-y, doi:10.1186/s12858-017-0088-y. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12858-017-0088-y)

[4. (Kimura2016CKAP4) Hirokazu Kimura, Katsumi Fumoto, Kensaku Shojima, Satoshi Nojima, Yoshihito Osugi, Hideo Tomihara, Hidetoshi Eguchi, Yasushi Shintani, Hiroko Endo, Masahiro Inoue, Yuichiro Doki, Meinoshin Okumura, Eiichi Morii, and Akira Kikuchi. Ckap4 is a dickkopf1 receptor and is involved in tumor progression. Journal of Clinical Investigation, 126(7):2689–2705, June 2016. URL: http://dx.doi.org/10.1172/jci84658, doi:10.1172/jci84658. This article has 126 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci84658)

[5. (Kimura2019CKAP4) Hirokazu Kimura, Hideki Yamamoto, Takeshi Harada, Katsumi Fumoto, Yoshihito Osugi, Ryota Sada, Natsumi Maehara, Hayato Hikita, Soichiro Mori, Hidetoshi Eguchi, Masahito Ikawa, Tetsuo Takehara, and Akira Kikuchi. Ckap4, a dkk1 receptor, is a biomarker in exosomes derived from pancreatic cancer and a molecular target for therapy. Clinical Cancer Research, 25(6):1936–1947, March 2019. URL: http://dx.doi.org/10.1158/1078-0432.ccr-18-2124, doi:10.1158/1078-0432.ccr-18-2124. This article has 91 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/1078-0432.ccr-18-2124)

[6. (Zhu2021RNABinding) Hong Zhu, Yanfeng Zhang, Chengliang Zhang, and Zhongshang Xie. Rna-binding profiles of ckap4 as an rna-binding protein in myocardial tissues. Frontiers in Cardiovascular Medicine, December 2021. URL: http://dx.doi.org/10.3389/fcvm.2021.773573, doi:10.3389/fcvm.2021.773573. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcvm.2021.773573)

[7. (Wang2021Plasmalemma) Yi Wang, Haitao Yu, Xiaozai Xie, Tuo Deng, Longyun Ye, Lijun Wu, Xiwei Ding, Zhen Yang, Qiandong Zhu, Junjian Li, Yihu Zheng, Zhengping Yu, and Gang Chen. Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the dkk1/ckap4/pi3k signaling pathway. Oncogene, 40(25):4324–4337, June 2021. URL: http://dx.doi.org/10.1038/s41388-021-01844-z, doi:10.1038/s41388-021-01844-z. This article has 22 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/s41388-021-01844-z)

[8. (Harada2020Palmitoylated) Takeshi Harada, Ryota Sada, Yoshito Osugi, Shinji Matsumoto, Tomoki Matsuda, Mitsuko Hayashi-Nishino, Takeharu Nagai, Akihiro Harada, and Akira Kikuchi. Palmitoylated ckap4 regulates mitochondrial functions through an interaction with vdac2 at er–mitochondria contact sites. Journal of Cell Science, November 2020. URL: http://dx.doi.org/10.1242/jcs.249045, doi:10.1242/jcs.249045. This article has 24 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.249045)

[9. (Lyu2018SENCRstabilizes) Qing Lyu, Suowen Xu, Yuyan Lyu, Mihyun Choi, Christine K. Christie, Orazio J. Slivano, Arshad Rahman, Zheng-Gen Jin, Xiaochun Long, Yawei Xu, and Joseph M. Miano. Sencrstabilizes vascular endothelial cell adherens junctions through interaction with ckap4. Proceedings of the National Academy of Sciences, 116(2):546–555, December 2018. URL: http://dx.doi.org/10.1073/pnas.1810729116, doi:10.1073/pnas.1810729116. This article has 83 citations.](https://doi.org/10.1073/pnas.1810729116)

[10. (Li2021CytoskeletonAssociated) Shuang-Xi Li, Juan Li, Li-Wei Dong, and Zhi-Yong Guo. Cytoskeleton-associated protein 4, a promising biomarker for tumor diagnosis and therapy. Frontiers in Molecular Biosciences, February 2021. URL: http://dx.doi.org/10.3389/fmolb.2020.552056, doi:10.3389/fmolb.2020.552056. This article has 17 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fmolb.2020.552056)

[11. (Zacharias2012Antiproliferative) David A. Zacharias, Matthew Mullen, and Sonia Lobo Planey. Antiproliferative factor-induced changes in phosphorylation and palmitoylation of cytoskeleton-associated protein-4 regulate its nuclear translocation and dna binding. International Journal of Cell Biology, 2012:1–13, 2012. URL: http://dx.doi.org/10.1155/2012/150918, doi:10.1155/2012/150918. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1155/2012/150918)