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. 2016 Nov 15;7(46):76224-76237.
doi: 10.18632/oncotarget.12779.

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  1   2 , Juan Du  1 , Yunling Wang  1 , Mingzi Yang  1 , Jianchao Gao  1 , Xiaofan Wei  1 , Weigang Fang  1   2 , Jun Zhan  1 , Hongquan Zhang  1
Affiliations

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 et al. Oncotarget. .

Abstract

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.

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

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Conflict of interest statement

CONFLICTS OF INTEREST

There is no conflicts of interest.

Figures

Figure 1
Figure 1. Kindlin-1 expression is correlated with CRC progression and patient outcome
Figure 2
Figure 2. Kindlin-1 promotes CRC cell proliferation in vitro and tumor growth in vivo
Figure 3
Figure 3. Kindlin-1 promotes CRC cell invasion and migration by stimulating an EMT phenotype
Figure 4
Figure 4. Kindlin-1 is required for the interaction of TβRI with Smad3 in CRC cells
Figure 5
Figure 5. Kindlin-1 activates TGF-β/Smad3 signaling in CRC cells
Figure 6
Figure 6. Kindlin-1 forms a complex with SARA, TβRI and Smad3 to activate TGF-β/Smad3 signaling in CRC cells
Figure 7
Figure 7. Kindlin-1 is required for TGF-β/Smad3 signaling in CRC progression - A working model
See this image and copyright information in PMC

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