Homophilic complex formation of CDCP1 via the extracellular CUB2 domain facilitates SFK activation and promotes cancer cell migration

Sawayama,Tadashi; Nakashima,Katsuhiko; Ichimura,Tohru; Sakai,Ryuichi; Uekita,Takamasa

doi:10.3892/or.2019.7271

Homophilic complex formation of CDCP1 via the extracellular CUB2 domain facilitates SFK activation and promotes cancer cell migration

Authors:
- Tadashi Sawayama
- Katsuhiko Nakashima
- Tohru Ichimura
- Ryuichi Sakai
- Takamasa Uekita
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Affiliations: Department of Applied Chemistry, National Defense Academy, Yokosuka 23908686, Japan, Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Tokyo 105‑0045, Japan
Published online on: August 8, 2019 https://doi.org/10.3892/or.2019.7271
Pages: 1507-1516

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Abstract

CUB domain‑containing protein 1 (CDCP1) is phosphorylated by Src family kinases (SFK), and is thought to serve an important role in tumor metastasis through downstream signaling subsequent to its interaction with protein kinase C δ. The present study investigated the mechanisms of activation for CDCP1 signaling, and demonstrated that CDCP1 is able to activate SFK via a homophilic complex of the extracellular complement C1r/C1s, urchin embryonic growth factor, bone morphogenetic protein 1 (CUB) 2 domain. Deletion of the extracellular CDCP1 region abolished homophilic complex formation of CDCP1 and the ability to promote cancer cell migration. When the culture medium was supplemented with recombinant CUB2 domain protein fused with maltose binding protein (rMBP‑CUB2), CDCP1 homophilic complex formation was effectively inhibited. rMBP‑CUB2 also inhibited SFK activation and the migratory capacity of invasive human lung adenocarcinoma A549 cells, and human pancreatic BxPC3 cells. These findings demonstrated a novel function for the extracellular CUB2 domain of CDCP1, promoting cancer cell migration via SFK activation on the plasma membrane. It was also indicated that the region blocking the homophilic binding site may be a potential therapeutic target against CDCP1‑dependent tumor invasion.

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