Cytoskeleton-Associated Protein 4: Functions Beyond the Endoplasmic Reticulum in Physiology and Disease

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.