title: Focal adhesion molecule Kindlin-1 mediates activation of TGF-β signaling by interacting with TGF-βRI, SARA and Smad3 in colorectal cancer cells.
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.
authors: Key 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.|Department Pathology, Peking University Health Science Center, Beijing 100191, China.
authors: Jinfeng
authors: J
authors: Kong
authors: Key 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.
authors: Juan
authors: J
authors: Du
authors: Key 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.
authors: Yunling
authors: Y
authors: Wang
authors: Key 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.
authors: Mingzi
authors: M
authors: Yang
authors: Key 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.
authors: Jianchao
authors: J
authors: Gao
authors: Key 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.
authors: Xiaofan
authors: X
authors: Wei
authors: Key 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.|Department Pathology, Peking University Health Science Center, Beijing 100191, China.
authors: Weigang
authors: W
authors: Fang
authors: Key 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.
authors: Jun
authors: J
authors: Zhan
authors: Key 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.
authors: Hongquan
authors: H
authors: Zhang
mesh_terms: D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C475301:FERMT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C116420:ZFYVE16 protein, human; D012697:Serine Endopeptidases
keywords: Kindlin-1; Smad anchor for receptor activation (SARA); Smad3; TGF-β receptor I; colorectal carcinoma