Cytoskeleton-associated protein 4 (CKAP4; also known as p63, CLIMP-63, or ERGIC-63) is a 63？kDa, reversibly palmitoylated and phosphorylated, type II transmembrane (TM) protein, originally identified as a resident of the endoplasmic reticulum (ER)/Golgi intermediate compartment (ERGIC). When localized to the ER, a major function of CKAP4 is to anchor rough ER to microtubules, organizing the overall structure of ER with respect to the microtubule network. There is also steadily accumulating evidence for diverse roles for CKAP4 localized outside the ER, including data demonstrating functionality of cell surface forms of CKAP4 in various cell types and of CKAP4 in the nucleus. We will review the recent studies that provide evidence for the existence of CKAP4 in multiple cellular compartments (i.e., ER, plasma membrane, and the nucleus) and discuss CKAP4’s role in the regulation of various physiological and pathological processes, such as interstitial cystitis, drug-induced cytotoxicity, pericullar proteolytic activity, and lung lipid homeostasis. 1. Introduction Cytoskeleton-associated protein 4 (CKAP4), also known as p63, CLIMP-63, and ERGIC-63, is a 63-kDa nonglycosylated, type II transmembrane protein that is reversibly palmitoylated during interference of intracellular protein transport and mitosis [1–5]. Hans-Peter Hauri and colleagues first identified CKAP4 in 1993 while studying morphogenesis of the endoplasmic reticulum (ER). They found CKAP4 to be a resident protein of the stable ER-Golgi intermediate compartment (ERGIC) and to show signs of being highly enriched in isolated ERGIC [2]. However, early studies following this initial discovery, used rabbit polyclonal antibodies and immunoelectron microscopy to demonstrate that CKAP4 was actually located in the rough ER where it functions as a microtubule-binding protein, anchoring the ER membranes to the microtubular cytoskeleton of epithelial cells in vivo and in vitro and maintaining the structure of the ER [2, 3, 6–8]. This ability made CKAP4 the first integral membrane protein capable of linking an organelle to microtubules and earned it the name cytoskeletal-linking membrane protein or CLIMP-63 [9]. Further investigation by mutagenesis demonstrated that the luminal segment of CKAP4 oligomerizes into α-helical complexes. These coiled-coil complexes prevent CKAP4 from being located at the nuclear envelope and mediate its specific localization in the reticular domain of the ER [9]. Currently, CKAP4 is known to also be present in the plasma membrane of vascular smooth muscle cells [10], bladder
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