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

被引：24

作者：

Kong, Jinfeng ^{[1
,2
]}

Du, Juan ^{[1
]}

Wang, Yunling ^{[1
]}

Yang, Mingzi ^{[1
]}

Gao, Jianchao ^{[1
]}

Wei, Xiaofan ^{[1
]}

Fang, Weigang ^{[1
,2
]}

Zhan, Jun ^{[1
]}

Zhang, Hongquan ^{[1
]}

机构：

[1] Peking Univ, Key Lab Carcinogenesis & Translat Res, State Key Lab Nat & Biomimet Drugs,Minist Educ, Dept Anat Histol & Embryol,Hlth Sci Ctr, Beijing 100191, Peoples R China

[2] Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100191, Peoples R China

来源：

ONCOTARGET | 2016年 / 7卷 / 46期

基金：

北京市自然科学基金; 中国国家自然科学基金;

关键词：

Kindlin-1; Colorectal carcinoma; TGF-beta receptor I; Smad3; Smad anchor for receptor activation (SARA); KINDLER SYNDROME PROTEIN; FYVE DOMAIN PROTEIN; GROWTH-FACTOR-BETA; STEM-CELLS; EXPRESSION; WNT; HOMOLOG;

D O I：

10.18632/oncotarget.12779

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Kindlin-1, an integrin-interacting protein, has been implicated in TGF-beta/Smad3 signaling. However, the molecular mechanism underlying Kindlin-1 regulation of TGF-beta/Smad3 signaling remains elusive. Here, we reported that Kindlin-1 is an important mediator of TGF-beta/Smad3 signaling by showing that Kindlin-1 physically interacts with TGF-beta receptor I (T beta RI), Smad anchor for receptor activation (SARA) and Smad3. Kindlin-1 is required for the interaction of Smad3 with T beta RI, Smad3 phosphorylation, nuclear translocation, and finally the activation of TGF-beta/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 T beta RI and thereby activates TGF-beta/Smad3 signaling. Thus, Kindlin-1 is a novel regulator of TGF-beta/Smad3 signaling and may also be a potential target for CRC therapeutics.

引用

页码：76224 / 76237

页数：14

共 31 条

[1] Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome [J].

Ashton, GHS ;

McLean, WHI ;

South, AP ;

Oyama, N ;

Smith, FJD ;

Al-Suwaid, R ;

Al ismaily, A ;

Atherton, DJ ;

Harwood, CA ;

Leigh, IM ;

Moss, C ;

Didona, B ;

Zambruno, G ;

Patrizi, A ;

Eady, RAJ ;

McGrath, JA .

JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2004, 122 (01) :78-83

[2] Lgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-Lived Gastric Units In Vitro [J].

Barker, Nick ;

Huch, Meritxell ;

Kujala, Pekka ;

van de Wetering, Marc ;

Snippert, Hugo J. ;

van Es, Johan H. ;

Sato, Toshiro ;

Stange, Daniel E. ;

Begthel, Harry ;

van den Born, Maaike ;

Danenberg, Esther ;

van den Brink, Stieneke ;

Korving, Jeroen ;

Abo, Arie ;

Peters, Peter J. ;

Wright, Nick ;

Poulsom, Richard ;

Clevers, Hans .

CELL STEM CELL, 2010, 6 (01) :25-36

[3] Differential expression of transforming growth factors-β1, -β2 and -β3 in human colon carcinoma [J].

Bellone, G ;

Carbone, A ;

Tibaudi, D ;

Mauri, F ;

Ferrero, I ;

Smirne, C ;

Suman, F ;

Rivetti, C ;

Migliaretti, G ;

Camandona, M ;

Palestro, G ;

Emanuelli, G ;

Rodeck, U .

EUROPEAN JOURNAL OF CANCER, 2001, 37 (02) :224-233

[4] EMT and MET in Metastasis: Where Are the Cancer Stem Cells? [J].

Brabletz, Thomas .

CANCER CELL, 2012, 22 (06) :699-701

[5] Cancer Statistics in China, 2015 [J].

Chen, Wanqing ;

Zheng, Rongshou ;

Baade, Peter D. ;

Zhang, Siwei ;

Zeng, Hongmei ;

Bray, Freddie ;

Jemal, Ahmedin ;

Yu, Xue Qin ;

He, Jie .

CA-A CANCER JOURNAL FOR CLINICIANS, 2016, 66 (02) :115-132

[6] Kindler Syndrome Pathogenesis and Fermitin Family Homologue 1 (Kindlin-1) Function [J].

D'Souza, Maria-Anna M. A. ;

Kimble, Roy M. ;

McMillan, James R. .

DERMATOLOGIC CLINICS, 2010, 28 (01) :115-+

[7] Digital Transcript Profile Analysis with aRNA-LongSAGE Validates FERMT1 As a Potential Novel Prognostic Marker for Colon Cancer [J].

Fan, Junwei ;

Yan, Dongwang ;

Teng, Mujian ;

Tang, Huamei ;

Zhou, Chongzhi ;

Wang, Xiaoliang ;

Li, Dawei ;

Qiu, Guoqiang ;

Peng, Zhihai .

CLINICAL CANCER RESEARCH, 2011, 17 (09) :2908-2918

[8] A GENETIC MODEL FOR COLORECTAL TUMORIGENESIS [J].

FEARON, ER ;

VOGELSTEIN, B .

CELL, 1990, 61 (05) :759-767

[9] Kindlin-1 and-2 Directly Bind the C-terminal Region of β Integrin Cytoplasmic Tails and Exert Integrin-specific Activation Effects [J].

Harburger, David S. ;

Bouaouina, Mohamed ;

Calderwood, David A. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (17) :11485-11497

[10] MicroRNA-200c modulates epithelial-to-mesenchymal transition (EMT) in human colorectal cancer metastasis [J].

Hur, Keun ;

Toiyama, Yuji ;

Takahashi, Masanobu ;

Balaguer, Francesc ;

Nagasaka, Takeshi ;

Koike, Junichi ;

Hemmi, Hiromichi ;

Koi, Minoru ;

Boland, C. Richard ;

Goel, Ajay .

GUT, 2013, 62 (09) :1315-1326

← 1 2 3 4 →