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The type II TGF-β receptor phosphorylates Tyr182 in the type I receptor to activate downstream Src signaling
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, Uppsala, Sweden.
Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Box 582, Uppsala, Sweden.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.ORCID iD: 0000-0001-6737-7230
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2022 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 15, no 760, article id eabp9521Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor–β (TGF-β) signaling has important roles during embryonic development and in tissue homeostasis. TGF-β ligands exert cellular effects by binding to type I (TβRI) and type II (TβRII) receptors and inducing both SMAD-dependent and SMAD-independent intracellular signaling pathways, the latter of which includes the activation of the tyrosine kinase Src. We investigated the mechanism by which TGF-β stimulation activates Src in human and mouse cells. Before TGF-β stimulation, inactive Src was complexed with TβRII. Upon TGF-β1 stimulation, TβRII associated with and phosphorylated TβRI at Tyr182. Binding of Src to TβRI involved the interaction of the Src SH2 domain with phosphorylated Tyr182 and the interaction of the Src SH3 domain with a proline-rich region in TβRI and led to the activation of Src kinase activity and Src autophosphorylation. TGF-β1–induced Src activation required the kinase activities of TβRII and Src but not that of TβRI. Activated Src also phosphorylated TβRI on several tyrosine residues, which may stabilize the binding of Src to the receptor. Src activation was required for the ability of TGF-β to induce fibronectin production and migration in human breast carcinoma cells and to induce α–smooth muscle actin and actin reorganization in mouse fibroblasts. Thus, TGF-β induces Src activation by stimulating a direct interaction with TβRI that depends on tyrosine phosphorylation of TβRI by TβRII.

Place, publisher, year, edition, pages
American Association for the Advancement of Science , 2022. Vol. 15, no 760, article id eabp9521
National Category
Cell and Molecular Biology
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URN: urn:nbn:se:umu:diva-201358DOI: 10.1126/scisignal.abp9521ISI: 000909193200002PubMedID: 36378749Scopus ID: 2-s2.0-85141940300OAI: oai:DiVA.org:umu-201358DiVA, id: diva2:1717120
Funder
EU, European Research Council, 787472Swedish Research Council, K2019-01598Swedish Research Council, 2015-02757Swedish Cancer Society, 18 0491Knut and Alice Wallenberg Foundation, 2012.0090ProstatacancerförbundetKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseRegion Västerbotten, ALF; 7003284Available from: 2022-12-07 Created: 2022-12-07 Last updated: 2023-09-05Bibliographically approved

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Landström, Maréne

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