CDCP1 promotes compensatory renal growth by integrating Src and Met signaling.

Affiliation

Kajiwara K(1), Yamano S(2), Aoki K(3), Okuzaki D(4), Matsumoto K(5), Okada M(6).
Author information:
(1)Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan [Email]
(2)Japan Bioassay Research Center, Japan Organization of Occupational Health and Safety, Kanagawa, Japan.
(3)Division of Quantitative Biology, Okazaki Institute for Integrative Bioscience, National Institute for Basic Biology, National Institutes of Natural Sciences, Aichi, Japan.
(4)Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
(5)Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
(6)Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan [Email]

Abstract

Compensatory growth of organs after loss of their mass and/or function is controlled by hepatocyte growth factor (HGF), but the underlying regulatory mechanisms remain elusive. Here, we show that CUB domain-containing protein 1 (CDCP1) promotes HGF-induced compensatory renal growth. Using canine kidney cells as a model of renal tubules, we found that HGF-induced temporal up-regulation of Src activity and its scaffold protein, CDCP1, and that the ablation of CDCP1 robustly abrogated HGF-induced phenotypic changes, such as morphological changes and cell growth/proliferation. Mechanistic analyses revealed that up-regulated CDCP1 recruits Src into lipid rafts to activate STAT3 associated with the HGF receptor Met, and activated STAT3 induces the expression of matrix metalloproteinases and mitogenic factors. After unilateral nephrectomy in mice, the Met-STAT3 signaling is transiently up-regulated in the renal tubules of the remaining kidney, whereas CDCP1 ablation attenuates regenerative signaling and significantly suppresses compensatory growth. These findings demonstrate that CDCP1 plays a crucial role in controlling compensatory renal growth by focally and temporally integrating Src and Met signaling.