Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A
The Src homology 2 (SH2) and SH3 domain-containing chicken tumor virus number 10 (CT10) regulator of kinase (Crk) adaptor proteins include three cellular members that serve as integral constituents of multiple receptor-linked signal transduction pathways. CrkI and CrkII are products of alternative R...
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| Format: | Article |
| Language: | English |
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Open Exploration Publishing Inc.
2023-06-01
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| Series: | Exploration of Immunology |
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| Online Access: | https://www.explorationpub.com/Journals/ei/Article/100399 |
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| author | Noah Isakov |
| author_facet | Noah Isakov |
| author_sort | Noah Isakov |
| collection | DOAJ |
| description | The Src homology 2 (SH2) and SH3 domain-containing chicken tumor virus number 10 (CT10) regulator of kinase (Crk) adaptor proteins include three cellular members that serve as integral constituents of multiple receptor-linked signal transduction pathways. CrkI and CrkII are products of alternative RNA-splicing which is transcribed from a single gene, while Crk-like (CrkL), which is highly homologous to CrkII, is encoded by a different gene. Thanks to their modular structure, the Crk adaptor proteins can simultaneously interact with activated receptors and a wide range of effector molecules, and orchestrate the assembly of complexes containing enzymes and substrates at the receptor site. They are involved in the regulation of a large number of cellular processes which control cell growth, differentiation, transformation, and apoptosis. Cell activation-dependent tyrosine phosphorylation of CrkII and CrkL serves as a major posttranslational modification mechanism that introduces conformational changes in the proteins by promoting an intramolecular interaction between the phosphotyrosine and the self SH2 domain. The resulting conformational change induces downregulation of CrkII- and CrkL-dependent biological processes. A second type of posttranslational modification mechanism regulates the structure and function of the CrkII adaptor protein by immunophilin-mediated protein isomerization. Two of the most abundant immunophilins in T lymphocytes which function as peptidyl-prolyl cis-trans isomerases (PPIases), namely cyclophilin A (CypA) and FK506-binding proteins (FKBPs), can associate with CrkII and catalyze its reciprocal cis-trans isomerization. This mechanism is of special importance for the regulation of T lymphocyte functions and for T cell-mediated immune responses, since immunophilin inhibitors, such as cyclosporin A (CsA) and FK506, function as immunosuppressive drugs that can prevent allotransplanted graft rejection. The present manuscript focuses on selected functions of Crk adaptor proteins, predominantly in T lymphocytes, and reviews in more detail the current knowledge on the immunophilin-dependent regulation of the structure and function of the CrkII adaptor protein. |
| first_indexed | 2024-03-12T23:15:12Z |
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| language | English |
| last_indexed | 2024-03-12T23:15:12Z |
| publishDate | 2023-06-01 |
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| series | Exploration of Immunology |
| spelling | doaj.art-34a57670a949423e9c116d18095046a22023-07-17T08:14:40ZengOpen Exploration Publishing Inc.Exploration of Immunology2768-66552023-06-0133217232https://doi.org/10.37349/ei.2023.00099Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin ANoah Isakov0https://orcid.org/0000-0002-1412-0957Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, IsraelThe Src homology 2 (SH2) and SH3 domain-containing chicken tumor virus number 10 (CT10) regulator of kinase (Crk) adaptor proteins include three cellular members that serve as integral constituents of multiple receptor-linked signal transduction pathways. CrkI and CrkII are products of alternative RNA-splicing which is transcribed from a single gene, while Crk-like (CrkL), which is highly homologous to CrkII, is encoded by a different gene. Thanks to their modular structure, the Crk adaptor proteins can simultaneously interact with activated receptors and a wide range of effector molecules, and orchestrate the assembly of complexes containing enzymes and substrates at the receptor site. They are involved in the regulation of a large number of cellular processes which control cell growth, differentiation, transformation, and apoptosis. Cell activation-dependent tyrosine phosphorylation of CrkII and CrkL serves as a major posttranslational modification mechanism that introduces conformational changes in the proteins by promoting an intramolecular interaction between the phosphotyrosine and the self SH2 domain. The resulting conformational change induces downregulation of CrkII- and CrkL-dependent biological processes. A second type of posttranslational modification mechanism regulates the structure and function of the CrkII adaptor protein by immunophilin-mediated protein isomerization. Two of the most abundant immunophilins in T lymphocytes which function as peptidyl-prolyl cis-trans isomerases (PPIases), namely cyclophilin A (CypA) and FK506-binding proteins (FKBPs), can associate with CrkII and catalyze its reciprocal cis-trans isomerization. This mechanism is of special importance for the regulation of T lymphocyte functions and for T cell-mediated immune responses, since immunophilin inhibitors, such as cyclosporin A (CsA) and FK506, function as immunosuppressive drugs that can prevent allotransplanted graft rejection. The present manuscript focuses on selected functions of Crk adaptor proteins, predominantly in T lymphocytes, and reviews in more detail the current knowledge on the immunophilin-dependent regulation of the structure and function of the CrkII adaptor protein.https://www.explorationpub.com/Journals/ei/Article/100399chicken tumor virus number 10 (ct10) regulator of kinase ii (crkii)crk adaptor proteinpeptidyl-prolyl cis-trans isomerase (ppiase)immunophilincyclophilin a (cypa)cyclosporin a (csa)t cell activationsignal transduction |
| spellingShingle | Noah Isakov Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A Exploration of Immunology chicken tumor virus number 10 (ct10) regulator of kinase ii (crkii) crk adaptor protein peptidyl-prolyl cis-trans isomerase (ppiase) immunophilin cyclophilin a (cypa) cyclosporin a (csa) t cell activation signal transduction |
| title | Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A |
| title_full | Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A |
| title_fullStr | Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A |
| title_full_unstemmed | Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A |
| title_short | Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A |
| title_sort | conformational and functional regulation of the chicken tumor virus number 10 ct10 regulator of kinase ii crkii adaptor protein by cyclophilin a |
| topic | chicken tumor virus number 10 (ct10) regulator of kinase ii (crkii) crk adaptor protein peptidyl-prolyl cis-trans isomerase (ppiase) immunophilin cyclophilin a (cypa) cyclosporin a (csa) t cell activation signal transduction |
| url | https://www.explorationpub.com/Journals/ei/Article/100399 |
| work_keys_str_mv | AT noahisakov conformationalandfunctionalregulationofthechickentumorvirusnumber10ct10regulatorofkinaseiicrkiiadaptorproteinbycyclophilina |