CKAP4

Official Full Name

cytoskeleton associated protein 4

Organism

Homo sapiens

GeneID

10970

Background

Enables RNA binding activity. Located in lipid droplet and rough endoplasmic reticulum. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

p63; CLIMP63; CLIMP-63; ERGIC-63;

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Detailed Information

Recent Research Progress

Cytoskeleton-associated protein 4 (CKAP4, also known as P63, CLIMP-63 and ERGIC-63) is a type II transmembrane protein that is reversibly palmitoylated. It was originally discovered to be a protein that localizes to the ER and binds to microtubules. Subsequently, CKAP4 displays a cell surface membrane localized to type II lung cells, bladder epithelial cells and vascular smooth muscle cells, in which it acts as a receptor for several ligands, including surface active protein A (SP-A), tissue fibrinolysis plasminogen activator (tPA) and anti-proliferative factor (APF). Recently, CKAP4 was identified as a novel Dickkopf1 (DKK1) binding protein on the surface membrane of Madin-Darby canine kidney (MDCK) cells, which is involved in tumor progression.

CKAP4 and HCC

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although many HCC patients can be treated with surgical resection or transcatheter arterial chemoembolization, the prognosis of this disease remains frustrating. Li et al. knocked down or overexpressed CKAP4 in HCC cells and passed Cell Counting Kit-8 (CCK- 8) and transwell assays to study cell proliferation, invasion and migration capabilities. The role of CKAP4 in HCC growth and metastasis was assessed using a mouse in vivo tumor model. The data demonstrated that HCC cells with high levels of CKAP4 were characterized by low proliferative capacity and low invasive potential. Interestingly, CKAP4 inhibited the activation of epidermal growth factor receptor (EGFR) signaling, which may partly explain the role of CKAP4 in the biological behavior of HCC cells. Further studies have shown that CKAP4 associated with EGFR in a basal state and the complex was reduced after EGF stimulation, resulting in the release of EGFR into the cytoplasm. Thus, these data demonstrate that expression of CKAP4 regulates the progression and metastasis of HCC and may provide therapeutic value for this tumor.

CKAP4 and ESCC

Esophageal squamous cell carcinoma (ESCC) is the predominant form of East and Eastern and Southern Africa, whereas esophageal adenocarcinoma is prevalent in North America and Europe. It was shown that CKAP4 acts as a DKK1 receptor in ESCC cells. The cancer genomic map data set showed that mRNA levels of DKK1 and CKAP4 were significantly elevated in tumor lesions compared to non-tumor areas. DKK1 bound to CKAP4 at an endogenous level. DKK1 induced internalization of CKAP4 and recycles it to the plasma membrane. AKT was activated in ESCC cells, where DKK1 was highly expressed and CKAP4 was localized to the plasma membrane. Knockout of DKK1 or CKAP4 inhibited AKT activity and cell proliferation in vitro as well as xenograft tumor formation. Wild-type CKAP4 or DKK1, but not the DKK1 mutant that failed to bind CKAP4, rescued the phenotype induced by CKAP4 or DKK1 knockdown, respectively. Anti-CKAP4 antibodies also inhibited AKT activity and inhibited xenograft tumor formation. In contrast, in ESCC cells in which DKK1 was marginally expressed, knockdown of CKAP4 or anti-CKAP4 antibodies neither affected AKT activity nor affects cell proliferation. These findings indicate that the DKKl-CKAP4 pathway promotes ESCC cell proliferation, and CKAP4 may represent a novel therapeutic target for ESCC expressing DKKl and CKAP4.

CKAP4 and ESCC

Common prostate adenocarcinomas have a lumen-type immune matrix, lack basic markers such as CKAP4 and high molecular weight cytokeratin, and diffusely express low molecular weight cytokeratin and androgen axis signaling markers. Tan et al. described a rare group of prostate adenocarcinomas that exhibit aberrant expression of CKAP4, a protein that is strongly expressed in prostate basal cells. Further studies indicate that prostate tumors expressing CKAP4 represent different subclasses of the molecule, and further investigation of this rare tumor type can yield important insights into the role of CKAP4 in prostate biology and prostate cancer cells.

In summary, there is increasing evidence that CKAP4 is involved in tumor progression. Further study of the role of CKAP4 in the mechanism of tumorigenesis contributes to the prevention and treatment of related cancers.

References:

Li Shuangxi, et al. CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EGFR signaling, Tumor Biology, 2014, 35(8): 7999-8005
Srinivas V, et al. ACTL6A is co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation and Poor Prognosis. Cancer Cell, 2017, 31(1):35–49
Hirokazu Kimura, et al. CKAP4 is a Dickkopf1 receptor and is involved in tumor progression. Clin Invest, 2016, 126(7):2689–2705
Naoki Shinno, et al. Activation of the Dickkopf1-CKAP4 pathway is associated with poor prognosis of esophageal cancer and anti-CKAP4 antibody may be a new therapeutic drug. Oncogene, 2018, 37:3471–3484
Akira Kikuchi, et al. The Dickkopf1-cytoskeleton-associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy. British Journal of Pharmacology, 2017, 174:4651–4665
Li ShuangXi, et al. Prognostic Significance of Cytoskeleton-Associated Membrane Protein 4 and Its Palmitoyl Acyltransferase DHHC2 in Hepatocellular Carcinoma. Cancer, 2014, 120:1520–31
Tan HsuehLi, et al. Prostate adenocarcinomas aberrantly expressing p63 are molecularly distinct from usual-type prostatic adenocarcinomas. Modern Pathology, 2015, 28: 446–456

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