Hsp90 and a tyrosine embedded in the Hsp90 recognition loop are required for the Fer tyrosine kinase activity |
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| Authors: | Elad Hikri Sally Shpungin Uri Nir |
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| Affiliation: | 1. Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Coordenação de Pesquisa, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil;2. Serviço de Hematologia, Hospital do Câncer I, INCA, RJ, Brazil;3. Programa de Carcinogênese Molecular, Coordenação de Pesquisa, INCA, RJ, Brazil;4. Fundação Oswaldo Cruz, Vice-presidência de Pesquisa e Laboratórios de Referência, RJ, Brazil;5. Laboratório de Biologia Molecular, Centro de Transplante de Medula Óssea, INCA, RJ, Brazil;1. Department of Comparative Biomedicine and Food Science, University of Padova, Legnaro, 35020 Padova, Italy;2. Clinic for Cattle, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany;3. Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland;4. Division of Experimental and Clinical Research, Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland;1. CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6201-506 Covilhã, Portugal;2. Department of Medical Sciences, Faculty of Health Sciences (FCS-UBI), University of Beira Interior, Covilhã, Portugal;3. Immunohemotherapy Service, Cova da Beira Hospital Centre (CHCB), Covilhã, Portugal |
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| Abstract: | Hsp90 is a key regulator of tyrosine kinases activity and is therefore considered as a promising target for intervention with deregulated signaling pathways in malignant cells. Here we describe a novel Hsp90 client — the intracellular tyrosine kinase, Fer, which is subjected to a unique regulatory regime by this chaperone. Inhibition of Hsp90 activity led to proteasomal degradation of the Fer enzyme. However, circumventing the dependence of Fer accumulation on Hsp90, revealed the dependence of the Fer kinase activity and its ability to phosphorylate Stat3 on the chaperon, expressing the necessity of Hsp90 for its function. Mutation analysis unveiled a tyrosine (Tyr616) embedded in the Hsp90 recognition loop, which is required for the kinase activity of Fer. Replacement of this tyrosine by phenylalanine (Y616F) disabled the auto-phosphorylation activity of Fer and abolished its ability to phosphorylate Stat3. Notably, surrounding the replaced Y616F with subtle mutations restored the auto and trans-phosphorylation activities of Fer suggesting that Y616 is not itself an essential auto-phosphorylation site of the kinase. Taken together, our results portray Hsp90 and its recognition loop as novel positive regulators of the Fer tyrosine kinase stability and activity. |
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