CKAP4 is a Dickkopf1 receptor and is involved in tumor progression.
Dickkopf1 (DKK1) is a secretory protein that antagonizes oncogenic Wnt signaling by binding to the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6). DKK1 may also regulate its own signaling to promote cancer cell proliferation, but the mechanism is not understood. Here, we identified cytoskeleton-associated protein 4 (CKAP4) as a DKK1 receptor and evaluated CKAP4-mediated DKK1 signaling in cancer cell proliferation. We determined that DKK1 binds CKAP4 and LRP6 with similar affinity but interacts with these 2 receptors with different cysteine-rich domains. DKK1 induced internalization of CKAP4 in a clathrin-dependent manner, further supporting CKAP4 as a receptor for DKK1. DKK1/CKAP4 signaling activated AKT by forming a complex between the proline-rich domain of CKAP4 and the Src homology 3 domain of PI3K, resulting in proliferation of normal cells and cancer cells. Expression of DKK1 and CKAP4 was frequent in tumor lesions of human pancreatic and lung cancers, and simultaneous expression of both proteins in patient tumors was negatively correlated with prognosis and relapse-free survival. An anti-CKAP4 antibody blocked the binding of DKK1 to CKAP4, suppressed AKT activity in a human cancer cell line, and attenuated xenograft tumor formation in immunodeficient mice. Together, our results suggest that CKAP4 is a potential therapeutic target for cancers that express both DKK1 and CKAP4.
Hirokazu
H
Kimura
Katsumi
K
Fumoto
Kensaku
K
Shojima
Satoshi
S
Nojima
Yoshihito
Y
Osugi
Hideo
H
Tomihara
Hidetoshi
H
Eguchi
Yasushi
Y
Shintani
Hiroko
H
Endo
Masahiro
M
Inoue
Yuichiro
Y
Doki
Meinoshin
M
Okumura
Eiichi
E
Morii
Akira
A
Kikuchi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004285:Dogs; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D015398:Signal Transduction
C081876:CKAP4 protein, human; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins