| First Author | Fritsch R | Year | 2013 |
| Journal | Cell | Volume | 153 |
| Issue | 5 | Pages | 1050-63 |
| PubMed ID | 23706742 | Mgi Jnum | J:198414 |
| Mgi Id | MGI:5496717 | Doi | 10.1016/j.cell.2013.04.031 |
| Citation | Fritsch R, et al. (2013) RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell 153(5):1050-63 |
| abstractText | RAS proteins are important direct activators of p110alpha, p110gamma, and p110delta type I phosphoinositide 3-kinases (PI3Ks), interacting via an amino-terminal RAS-binding domain (RBD). Here, we investigate the regulation of the ubiquitous p110beta isoform of PI3K, implicated in G-protein-coupled receptor (GPCR) signaling, PTEN-loss-driven cancers, and thrombocyte function. Unexpectedly, RAS is unable to interact with p110beta, but instead RAC1 and CDC42 from the RHO subfamily of small GTPases bind and activate p110beta via its RBD. In fibroblasts, GPCRs couple to PI3K through Dock180/Elmo1-mediated RAC activation and subsequent interaction with p110beta. Cells from mice carrying mutations in the p110beta RBD show reduced PI3K activity and defective chemotaxis, and these mice are resistant to experimental lung fibrosis. These findings revise our understanding of the regulation of type I PI3K by showing that both RAS and RHO family GTPases directly regulate distinct ubiquitous PI3K isoforms and that RAC activates p110beta downstream of GPCRs. |
