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Ligand-specific regulation of transforming growth factor beta superfamily factors by leucine-rich repeats and immunoglobulin-like domains proteins
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0003-3502-5948
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.ORCID iD: 0000-0001-6891-6996
2023 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 8, article id e0289726Article in journal (Refereed) Published
Abstract [en]

Leucine-rich repeats and immunoglobulin-like domains (LRIG) are transmembrane proteins shown to promote bone morphogenetic protein (BMP) signaling in Caenorhabditis elegans, Drosophila melanogaster, and mammals. BMPs comprise a subfamily of the transforming growth factor beta (TGFβ) superfamily, or TGFβ family, of ligands. In mammals, LRIG1 and LRIG3 promote BMP4 signaling. BMP6 signaling, but not BMP9 signaling, is also regulated by LRIG proteins, although the specific contributions of LRIG1, LRIG2, and LRIG3 have not been investigated, nor is it known whether other mammalian TGFβ family members are regulated by LRIG proteins. To address these questions, we took advantage of Lrig-null mouse embryonic fibroblasts (MEFs) with doxycycline-inducible LRIG1, LRIG2, and LRIG3 alleles, which were stimulated with ligands representing all the major TGFβ family subgroups. By analyzing the signal mediators pSmad1/5 and pSmad3, as well as the induction of Id1 expression, we showed that LRIG1 promoted BMP2, BMP4, and BMP6 signaling and suppressed GDF7 signaling; LRIG2 promoted BMP2 and BMP4 signaling; and LRIG3 promoted BMP2, BMP4, BMP6, and GDF7 signaling. BMP9 and BMP10 signaling was not regulated by individual LRIG proteins, however, it was enhanced in Lrig-null cells. LRIG proteins did not regulate TGFβ1-induced pSmad1/5 signaling, or GDF11- or TGFβ1-induced pSmad3 signaling. Taken together, our results show that some, but not all, TGFβ family ligands are regulated by LRIG proteins and that the three LRIG proteins display differential regulatory effects. LRIG proteins thereby provide regulatory means for the cell to further diversify the signaling outcomes generated by a limited number of TGFβ family ligands and receptors.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2023. Vol. 18, no 8, article id e0289726
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-214058DOI: 10.1371/journal.pone.0289726ISI: 001055176800011PubMedID: 37603563Scopus ID: 2-s2.0-85168488332OAI: oai:DiVA.org:umu-214058DiVA, id: diva2:1794550
Funder
Swedish Cancer Society, 21 1583 PjThe Kempe Foundations, JCK-1829Umeå University, RV-967035Region Västerbotten, RV-967035Available from: 2023-09-06 Created: 2023-09-06 Last updated: 2023-09-18Bibliographically approved

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Abdullah Nasir, AhmadHerdenberg, CarlHedman, Håkan

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