Src-mediated phosphorylation converts FHL1 from tumor suppressor to tumor promoter
| Autor: | Qingrui Sun, Jing Zhang, Xiaofan Wei, Feng Li, Lihua Ding, Yan Tang, Jun Zhan, Xiang Wang, Hongquan Zhang, Yang Yuan, Qinong Ye |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
animal structures Lung Neoplasms Time Factors Active Transport Cell Nucleus Mice Nude Muscle Proteins Uterine Cervical Neoplasms Adenocarcinoma of Lung macromolecular substances Biology Binding Competitive Article Focal adhesion 03 medical and health sciences Cell Movement Animals Humans Neoplasm Invasiveness Phosphorylation Transcription factor Research Articles Cell Proliferation Mice Inbred BALB C Cell growth Tumor Suppressor Proteins Intracellular Signaling Peptides and Proteins Membrane Proteins Cell Biology LIM Domain Proteins Actin cytoskeleton Neoplasm Proteins Tumor Burden Cell biology Repressor Proteins src-Family Kinases 030104 developmental biology Female Signal transduction Tyrosine kinase HeLa Cells Protein Binding Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.201708064 |
| Popis: | Wang et al. unveil a new mechanism by which Src may function as an oncogene. Phosphorylation of FHL1 by Src triggers the translocation of FHL1 to the nucleus, where it regulates the activity of the transcription factor BCLAF1 to promote tumor cell growth and loses the ability to regulate cell adhesion and suppress growth. FHL1 has been recognized for a long time as a tumor suppressor protein that associates with both the actin cytoskeleton and the transcriptional machinery. We present in this study a paradigm that phosphorylated FHL1 functions as an oncogenic protein by promoting tumor cell proliferation. The cytosolic tyrosine kinase Src interacts with and phosphorylates FHL1 at Y149 and Y272, which switches FHL1 from a tumor suppressor to a cell growth accelerator. Phosphorylated FHL1 translocates into the nucleus, where it binds to the transcription factor BCLAF1 and promotes tumor cell growth. Importantly, the phosphorylation of FHL1 is increased in tissues from lung adenocarcinoma patients despite the down-regulation of total FHL1 expression. Kindlin-2 was found to interact with FHL1 and recruit FHL1 to focal adhesions. Kindlin-2 competes with Src for binding to FHL1 and suppresses Src-mediated FHL1 phosphorylation. Collectively, we demonstrate that FHL1 can either suppress or promote tumor cell growth depending on the status of the sites for phosphorylation by Src. |
| Databáze: | OpenAIRE |
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