Differential sensitivity of Src-family kinases to activation by SH3 domain displacement.
Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4140816?pdf=render |
| _version_ | 1828465265239654400 |
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| author | Jamie A Moroco Jodi K Craigo Roxana E Iacob Thomas E Wales John R Engen Thomas E Smithgall |
| author_facet | Jamie A Moroco Jodi K Craigo Roxana E Iacob Thomas E Wales John R Engen Thomas E Smithgall |
| author_sort | Jamie A Moroco |
| collection | DOAJ |
| description | Src-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo. |
| first_indexed | 2024-12-11T03:29:44Z |
| format | Article |
| id | doaj.art-e14dcc7fe6fa4ec0a53c9671ea2bcb36 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T03:29:44Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e14dcc7fe6fa4ec0a53c9671ea2bcb362022-12-22T01:22:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0198e10562910.1371/journal.pone.0105629Differential sensitivity of Src-family kinases to activation by SH3 domain displacement.Jamie A MorocoJodi K CraigoRoxana E IacobThomas E WalesJohn R EngenThomas E SmithgallSrc-family kinases (SFKs) are non-receptor protein-tyrosine kinases involved in a variety of signaling pathways in virtually every cell type. The SFKs share a common negative regulatory mechanism that involves intramolecular interactions of the SH3 domain with the PPII helix formed by the SH2-kinase linker as well as the SH2 domain with a conserved phosphotyrosine residue in the C-terminal tail. Growing evidence suggests that individual SFKs may exhibit distinct activation mechanisms dictated by the relative strengths of these intramolecular interactions. To elucidate the role of the SH3:linker interaction in the regulation of individual SFKs, we used a synthetic SH3 domain-binding peptide (VSL12) to probe the sensitivity of downregulated c-Src, Hck, Lyn and Fyn to SH3-based activation in a kinetic kinase assay. All four SFKs responded to VSL12 binding with enhanced kinase activity, demonstrating a conserved role for SH3:linker interaction in the control of catalytic function. However, the sensitivity and extent of SH3-based activation varied over a wide range. In addition, autophosphorylation of the activation loops of c-Src and Hck did not override regulatory control by SH3:linker displacement, demonstrating that these modes of activation are independent. Our results show that despite the similarity of their downregulated conformations, individual Src-family members show diverse responses to activation by domain displacement which may reflect their adaptation to specific signaling environments in vivo.http://europepmc.org/articles/PMC4140816?pdf=render |
| spellingShingle | Jamie A Moroco Jodi K Craigo Roxana E Iacob Thomas E Wales John R Engen Thomas E Smithgall Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. PLoS ONE |
| title | Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. |
| title_full | Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. |
| title_fullStr | Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. |
| title_full_unstemmed | Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. |
| title_short | Differential sensitivity of Src-family kinases to activation by SH3 domain displacement. |
| title_sort | differential sensitivity of src family kinases to activation by sh3 domain displacement |
| url | http://europepmc.org/articles/PMC4140816?pdf=render |
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