RRC ID 47732
著者 Kimura H, Fumoto K, Shojima K, Nojima S, Osugi Y, Tomihara H, Eguchi H, Shintani Y, Endo H, Inoue M, Doki Y, Okumura M, Morii E, Kikuchi A.
タイトル CKAP4 is a Dickkopf1 receptor and is involved in tumor progression.
ジャーナル J Clin Invest
Abstract 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.
巻・号 126(7)
ページ 2689-705
公開日 2016-7-1
DOI 10.1172/JCI84658
PII 84658
PMID 27322059
PMC PMC4922689
MeSH Adult Aged Aged, 80 and over Animals Cell Line Cell Line, Tumor Cell Proliferation Dogs Female Gene Expression Regulation, Neoplastic* Hep G2 Cells Humans Intercellular Signaling Peptides and Proteins / metabolism* Lung Neoplasms / metabolism* Male Membrane Proteins / metabolism* Mice Mice, Inbred BALB C Mice, Nude Middle Aged Neoplasm Recurrence, Local Neoplasm Transplantation Pancreatic Neoplasms / metabolism* Protein Binding Protein Domains Signal Transduction
IF 11.864
引用数 48
WOS 分野 MEDICINE, RESEARCH & EXPERIMENTAL
リソース情報
遺伝子材料 CSII-CMV-MCS-IRES2-Bsd (RDB04385) CS-RfA-EVBsd (RDB06090) pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393)