Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer

• Published in: Oncogene Vol. 37; no. 2; pp. 263 - 270
• Main Authors: Ando, T, Charindra, D, Shrestha, M, Umehara, H, Ogawa, I, Miyauchi, M, Takata, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.01.2018; Nature Publishing Group
• Subjects: 13/95; 38/109; 42/89; 631/67/395; 631/80/83/2360; 82/80; Actin; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Apoptosis; Cancer; Care and treatment; CD63 antigen; Cell activation; Cell Biology; Cell growth; Cell Line, Tumor; Cell Nucleus; Cell proliferation; Cell Proliferation - genetics; Connective tissue growth factor; Diagnosis; Dosage and administration; Gene Knockdown Techniques; Gene mutation; HEK293 Cells; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Matrix metalloproteinase inhibitors; Medicine; Medicine & Public Health; Metalloproteinase; Neoplasms - genetics; Neoplasms - pathology; Nuclear transport; Oncology; Phosphoproteins - genetics; Phosphoproteins - metabolism; Phosphorylation; Protein transport; RhoA protein; RNA, Small Interfering - metabolism; short-communication; Signal Transduction - genetics; Tissue inhibitor of metalloproteinase 1; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissues; Trans-Activators; Transcription Factors; Yes-associated protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.321

Tissue inhibitor of metalloproteinase-1 (TIMP-1), a member of the TIMP family (TIMP-1 to 4), is highly expressed in various types of cancer and forms a complex with its receptor CD63 and Integrin β1. However, the precise oncogenic mechanism of TIMP-1 remains unclear. Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) are transcription co-activators enhancing the transcription of specific genes related to cell proliferation. But the mechanism of aberrant YAP/TAZ activation in cancer is not fully understood. Here, we showed that TIMP-1 activates YAP/TAZ as novel downstream targets to promote cell proliferation. The TIMP-1-CD63-Integrin β1 axis activates Src and promotes RhoA-mediated F-actin assembly, leading to LATS1/2 inactivation. This results in under-phosphorylation, protein stabilization and nuclear translocation of YAP/TAZ (YAP/TAZ activation); CTGF production; and cell proliferation. Furthermore, the TIMP-1-YAP/TAZ axis is aberrantly activated in various types of cancer cells or tissues. TIMP-1 knockdown inhibits cell proliferation through YAP/TAZ inactivation in cancer cells. This study found that TIMP-1 accelerates cell proliferation through YAP/TAZ activation in cancer, and suggests the TIMP-1-YAP/TAZ axis may be a novel potential drug target for cancer patients.