| First Author | Seo JH | Year | 2009 |
| Journal | Mol Cell Biol | Volume | 29 |
| Issue | 11 | Pages | 3076-87 |
| PubMed ID | 19307307 | Mgi Jnum | J:149152 |
| Mgi Id | MGI:3847828 | Doi | 10.1128/MCB.01686-08 |
| Citation | Seo JH, et al. (2009) Structural and functional basis of a role for CRKL in a fibroblast growth factor 8-induced feed-forward loop. Mol Cell Biol 29(11):3076-87 |
| abstractText | The adapter protein CRKL is required for the normal development of multiple tissues that rely on fibroblast growth factor 8 (FGF8). The precise role of CRKL in receptor signaling has been unclear, however. To address this issue, we first modeled the three-dimensional structure of CRKL by molecular dynamics. By taking advantage of structural simulations, we performed in silico analysis of the interactions of the autophosphorylation sites of FGR receptor 1 (FGFR1) with the SH2 domain of CRKL or a highly related protein, CRK. As predicted by simulations, we confirm the specific physical interaction of phosphorylated Y463 (pY463) in FGFR1 with the CRKL SH2 domain at an affinity approximately 30-fold stronger than that of CRK. We also provide evidence that interactions outside of the core YXXP motif have a significant impact on physical association, which is consistent with predictions from molecular-dynamics simulations. Furthermore, we identify CRKL as an essential component of an FGF8-induced feed-forward loop permissive for efficient activation of the mitogen-activated protein kinase Erk1/2, as well as FGF8-induced anchorage-independent cell growth, using Crkl-deficient cells or a pY463 synthetic peptide. Although many cells generally require cell-matrix adhesion, our results demonstrate that CRKL permits cells to bypass the strict need for adhesion in response to FGF8 through direct interaction with receptor. |
