A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane Cláudia Almeida Loureiro1,2 · Francisco R. Pinto2,3 · Patrícia Barros1,2 · Paulo Matos1,2,3 · Peter Jordan1,2 Received: 1 July 2019 / Revised: 6 December 2019 / Accepted: 2 January 2020 © Springer Nature Switzerland AG 2020
Abstract Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the recessive genetic disease cystic fibrosis, where the chloride transport across the apical membrane of epithelial cells mediated by the CFTR protein is impaired. CFTR protein trafficking to the plasma membrane (PM) is the result of a complex interplay between the secretory and membrane recycling pathways that control the number of channels present at the membrane. In addition, the ion transport activity of CFTR at the PM is modulated through post-translational protein modifications. Previously we described that spleen tyrosine kinase (SYK) phosphorylates a specific tyrosine residue in the nucleotide-binding domain 1 domain and this modification can regulate the PM abundance of CFTR. Here we identified the underlying biochemical mechanism using peptide pull-down assays followed by mass spectrometry. We identified in bronchial epithelial cells that the adaptor protein SHC1 recognizes tyrosine-phosphorylated CFTR through its phosphotyrosine-binding domain and that the formation of a complex between SHC1 and CFTR is induced at the PM in the presence of activated SYK. The depletion of endogenous SHC1 expression was sufficient to promote an increase in CFTR at the PM of these cells. The results identify a SYK/SHC1 pathway that regulates the PM levels of CFTR channels, contributing to a better understanding of how CFTR-mediated chloride secretion is regulated. Keywords CFTR · Chloride co-transport · Membrane traffic · Protein phosphorylation · SHC1 · SYK
Introduction Cystic fibrosis (CF) is the most common autosomal recessive disorder in the Caucasian population affecting more than 70,000 individuals worldwide, with an estimated incidence of one in 2500–4000 newborns [1]. CF is a multisystem Paulo Matos and Peter Jordan contributed equally. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03448-4) contains supplementary material, which is available to authorized users. * Peter Jordan [email protected]‑saude.pt 1
Department of Human Genetics, National Health Institute ‘Dr. Ricardo Jorge’, Avenida Padre Cruz, 1649‑016 Lisbon, Portugal
2
BioISI‑Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
3
Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal
disease affecting several organs and tissues caused by dysfunction of a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). This gene encodes the CFTR protein that functions as a chloride (Cl−) channel in the apic
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