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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Conwell, Michael D. Johnson, Derrick E. Ranahan, William P. Wells, Clark D. Bringman, Lauren R. Adler, Jacob J. Heller, Brigitte L. Sun, Yang Hudmon, Andy |
| Description | Author Affiliation: Adler JJ ( Department of Biochemistry and Molecular Biology, Department of Ophthalmology, Glick Eye Institute, and Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202.); |
| Abstract | Large tumor suppressor (LATS)1/2 protein kinases transmit Hippo signaling in response to intercellular contacts and serum levels to limit cell growth via the inhibition of Yes-associated protein (YAP). Here low serum and high LATS1 activity are found to enhance the levels of the 130-kDa isoform of angiomotin (Amot130) through phosphorylation by LATS1/2 at serine 175, which then forms a binding site for 14-3-3. Such phosphorylation, in turn, enables the ubiquitin ligase atrophin-1 interacting protein (AIP)4 to bind, ubiquitinate, and stabilize Amot130. Consistently, the Amot130 (S175A) mutant, which lacks LATS phosphorylation, bound AIP4 poorly under all conditions and showed reduced stability. Amot130 and AIP4 also promoted the ubiquitination and degradation of YAP in response to serum starvation, unlike Amot130 (S175A). Moreover, silencing Amot130 expression blocked LATS1 from inhibiting the expression of connective tissue growth factor, a YAP-regulated gene. Concordant with phosphorylated Amot130 specifically mediating these effects, wild-type Amot130 selectively induced YAP phosphorylation and reduced transcription of connective tissue growth factor in an AIP4-dependent manner versus Amot130 (S175A). Further, Amot130 but not Amot130 (S175A) strongly inhibited the growth of MDA-MB-468 breast cancer cells. The dominant-negative effects of Amot130 (S175A) on YAP signaling also support that phosphorylated Amot130 transduces Hippo signaling. Likewise, Amot130 expression provoked premature growth arrest during mammary cell acini formation, whereas Amot130 (S175A)-expressing cells formed enlarged and poorly differentiated acini. Taken together, the phosphorylation of Amot130 by LATS is found to be a key feature that enables it to inhibit YAP-dependent signaling and cell growth. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 43 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-10-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Adaptor Proteins, Signal Transducing Metabolism Cell Proliferation Drug Effects Culture Media, Serum-Free Pharmacology Intercellular Signaling Peptides And Proteins Membrane Proteins Phosphoproteins Protein-Serine-Threonine Kinases Tumor Suppressor Proteins 14-3-3 Proteins Genetics Amino Acid Sequence Animals Binding Sites Blotting, Western Cell Line Cell Line, Tumor HEK293 Cells MCF-7 Cells Microscopy, Confocal Mutation Phosphorylation Protein Binding RNA Interference Repressor Proteins Reverse Transcriptase Polymerase Chain Reaction Serine Transcription, Genetic Ubiquitin-Protein Ligases Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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