Research Papers:

Focal adhesion molecule Kindlin-1 mediates activation of TGF-β signaling by interacting with TGF-βRI, SARA and Smad3 in colorectal cancer cells

Jinfeng Kong, Juan Du, Yunling Wang, Mingzi Yang, Jianchao Gao, Xiaofan Wei, Weigang Fang, Jun Zhan and Hongquan Zhang _

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Oncotarget. 2016; 7:76224-76237. https://doi.org/10.18632/oncotarget.12779

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Jinfeng Kong1,2,*, Juan Du1,*, Yunling Wang1, Mingzi Yang1, Jianchao Gao1, Xiaofan Wei1, Weigang Fang1,2, Jun Zhan1, Hongquan Zhang1

1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing 100191, China

2Department Pathology, Peking University Health Science Center, Beijing 100191, China

*These authors have contributed equally to this work

Correspondence to:

Hongquan Zhang, email: Hongquan.Zhang@bjmu.edu.cn

Weigang Fang, email: wgfang@bjmu.edu.cn

Jun Zhan, email: Zhanjun@bjmu.edu.cn

Keywords: Kindlin-1, colorectal carcinoma, TGF-β receptor I, Smad3, Smad anchor for receptor activation (SARA)

Received: August 17, 2016    Accepted: October 05, 2016    Published: October 20, 2016


Kindlin-1, an integrin-interacting protein, has been implicated in TGF-β/Smad3 signaling. However, the molecular mechanism underlying Kindlin-1 regulation of TGF-β/Smad3 signaling remains elusive. Here, we reported that Kindlin-1 is an important mediator of TGF-β/Smad3 signaling by showing that Kindlin-1 physically interacts with TGF-β receptor I (TβRI), Smad anchor for receptor activation (SARA) and Smad3. Kindlin-1 is required for the interaction of Smad3 with TβRI, Smad3 phosphorylation, nuclear translocation, and finally the activation of TGF-β/Smad3 signaling pathway. Functionally, Kindlin-1 promoted colorectal cancer (CRC) cell proliferation in vitro and tumor growth in vivo, and was also required for CRC cell migration and invasion via an epithelial to mesenchymal transition. Kindlin-1 was found to be increased with the CRC progression from stages I to IV. Importantly, raised expression level of Kindlin-1 correlates with poor outcome in CRC patients. Taken together, we demonstrated that Kindlin-1 promotes CRC progression by recruiting SARA and Smad3 to TβRI and thereby activates TGF-β/Smad3 signaling. Thus, Kindlin-1 is a novel regulator of TGF-β/Smad3 signaling and may also be a potential target for CRC therapeutics.

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