Cytoskeleton-Associated Protein 4, a Promising Biomarker for Tumor Diagnosis and Therapy

Abstract

Cytoskeleton-associated protein 4 (CKAP4) is located in the rough endoplasmic reticulum (ER) and plays an important role in stabilizing the structure of ER. Meanwhile, CKAP4 is also found to act as an activated receptor at the cell surface. The multifunction of CKAP4 was gradually discovered with growing research evidence. In addition to the involvement in various physiological events including cell proliferation, cell migration, and stabilizing the structure of ER, CKAP4 has been implicated in tumorigenesis. However, the role of CKAP4 is still controversial in tumor biology, which may be related to different signal transduction pathways mediated by binding to different ligands in various microenvironments. Interestingly, CKAP4 has been recently recognized as a serological marker of several tumors and CKAP4 is expected to be a tumor therapeutic target. Therefore, deciphering the gene status, expression regulation, functions of CKAP4 in different diseases may shed new light on CKAP4-based cancer diagnosis and therapeutic strategy. This review discusses the publications that describe CKAP4 in various diseases, especially on tumor promotion and suppression, and provides a detailed discussion on the discrepancy.

Keywords: CKAP4; receptor; serological marker; tumor therapy; tumorigenesis.

FIGURE 1

Structure characteristics of human CKAP4 protein. It contains three regions, an intracellular region, TM region, and an extracellular region. The intracellular region is enlarged, showing important amino acids site or domain. EBD, ER binding domain; MBD, microtubule binding domain; TM, transmembrane; LZ, leucine zipper; Ser, serine; Cys, cysteine; Tyr, tyrosine; Arg, arginine.

FIGURE 2

The mechanism of CKAP4 regulating cell proliferation. Palmitoylated CKAP4 translocates from ER to PM. At the PM, CKAP4 binding its ligands APF and DKK-1, CKAP4 might undergo depalmitoylation. a: APF binding to CKAP4 induces phosphorylation of CKAP4, and the phosphorylated CKAP4 translocates to the nucleus, then changes related genes transcription, and plays an antiproliferation effect. b: The phosphorylated CKAP4 decreases AKT phosphorylation and then inhibits proliferation. c: Upon the CRD-1 of DKK-1 binding to CKAP4, CKAP4 binds to the p85α subunit of PI-3K to activate PI3K/AKT signaling and stimulate cell proliferation. d: DKK1 is a potent β-catenin-dependent Wnt signaling antagonist.