HYPOTHESIS: Do LRIG Proteins Regulate Stem Cell Quiescence by Promoting BMP Signaling?

Overview

Journal Stem Cell Rev Rep

Publisher Springer

Specialty Cell Biology

Date 2022 Aug 15

PMID 35969315

Authors

Carl Herdenberg

Hakan Hedman

Affiliations

Soon will be listed here.

Abstract

Leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins are evolutionarily conserved integral membrane proteins. Mammalian LRIG1 regulates stem cell quiescence in various tissue compartments, including compartments in the epidermis, oral mucosa, intestines, neural system, and incisors. The planarian LRIG1 homolog regulates the quiescence of multipotent neoblasts. The mechanism through which LRIG proteins regulate stem cell quiescence has not been well documented, although it is generally assumed that LRIG1 regulates the epidermal growth factor receptor (EGFR) or other receptor tyrosine kinases. However, Lrig-null (Lrig1-/-;Lrig2-/-; and Lrig3-/-) mouse embryonic fibroblasts (MEFs) have been recently found to exhibit apparently normal receptor tyrosine kinase functions. Moreover, bone morphogenetic protein (BMP) signaling has been shown to depend on LRIG1 and LRIG3 expression. BMPs are well-known regulators of stem cell quiescence. Here, we hypothesize that LRIG1 might regulate stem cell quiescence by promoting BMP signaling. HYPOTHESIS: Based on recent findings, it is hypothesized that LRIG1 regulates stem cell quiescence in mammalian tissues as well as in planarian neoblasts by promoting BMP signaling.

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References

Lopez-Rovira T, Chalaux E, Massague J, Rosa J, Ventura F . Direct binding of Smad1 and Smad4 to two distinct motifs mediates bone morphogenetic protein-specific transcriptional activation of Id1 gene. J Biol Chem. 2001; 277(5):3176-85. DOI: 10.1074/jbc.M106826200. View

Zhang G, Ferg M, Lubke L, Takamiya M, Beil T, Gourain V . Bone morphogenetic protein signaling regulates Id1-mediated neural stem cell quiescence in the adult zebrafish brain via a phylogenetically conserved enhancer module. Stem Cells. 2020; 38(7):875-889. DOI: 10.1002/stem.3182. View

Hollnagel A, Oehlmann V, Heymer J, Ruther U, Nordheim A . Id genes are direct targets of bone morphogenetic protein induction in embryonic stem cells. J Biol Chem. 1999; 274(28):19838-45. DOI: 10.1074/jbc.274.28.19838. View

Page M, Lombard P, Ng F, Gottgens B, Jensen K . The epidermis comprises autonomous compartments maintained by distinct stem cell populations. Cell Stem Cell. 2013; 13(4):471-82. PMC: 3793873. DOI: 10.1016/j.stem.2013.07.010. View

Genander M, Cook P, Ramskold D, Keyes B, Mertz A, Sandberg R . BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages. Cell Stem Cell. 2014; 15(5):619-33. PMC: 4276600. DOI: 10.1016/j.stem.2014.09.009. View

Neirinckx V, Hedman H, Niclou S . Harnessing LRIG1-mediated inhibition of receptor tyrosine kinases for cancer therapy. Biochim Biophys Acta Rev Cancer. 2017; 1868(1):109-116. DOI: 10.1016/j.bbcan.2017.02.007. View

Guo D, Holmlund C, Henriksson R, Hedman H . The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics. 2004; 84(1):157-65. DOI: 10.1016/j.ygeno.2004.01.013. View

Gumienny T, MacNeil L, Zimmerman C, Wang H, Chin L, Wrana J . Caenorhabditis elegans SMA-10/LRIG is a conserved transmembrane protein that enhances bone morphogenetic protein signaling. PLoS Genet. 2010; 6(5):e1000963. PMC: 2873917. DOI: 10.1371/journal.pgen.1000963. View

Richmond C, Shah M, Carlone D, Breault D . An enduring role for quiescent stem cells. Dev Dyn. 2016; 245(7):718-26. PMC: 4912863. DOI: 10.1002/dvdy.24416. View

10.

Rondahl V, Holmlund C, Karlsson T, Wang B, Faraz M, Henriksson R . Lrig2-deficient mice are protected against PDGFB-induced glioma. PLoS One. 2013; 8(9):e73635. PMC: 3762791. DOI: 10.1371/journal.pone.0073635. View

11.

Batts L, Polk D, DuBois R, Kulessa H . Bmp signaling is required for intestinal growth and morphogenesis. Dev Dyn. 2006; 235(6):1563-70. DOI: 10.1002/dvdy.20741. View

12.

Hedges S, Marin J, Suleski M, Paymer M, Kumar S . Tree of life reveals clock-like speciation and diversification. Mol Biol Evol. 2015; 32(4):835-45. PMC: 4379413. DOI: 10.1093/molbev/msv037. View

13.

Byrd K, Piehl N, Patel J, Huh W, Sequeira I, Lough K . Heterogeneity within Stratified Epithelial Stem Cell Populations Maintains the Oral Mucosa in Response to Physiological Stress. Cell Stem Cell. 2019; 25(6):814-829.e6. PMC: 6925542. DOI: 10.1016/j.stem.2019.11.005. View

14.

Qi Z, Li Y, Zhao B, Xu C, Liu Y, Li H . BMP restricts stemness of intestinal Lgr5 stem cells by directly suppressing their signature genes. Nat Commun. 2017; 8:13824. PMC: 5227110. DOI: 10.1038/ncomms13824. View

15.

Howe J, Roth S, Ringold J, Summers R, Jarvinen H, Sistonen P . Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998; 280(5366):1086-8. DOI: 10.1126/science.280.5366.1086. View

16.

Clevers H, Watt F . Defining Adult Stem Cells by Function, not by Phenotype. Annu Rev Biochem. 2018; 87:1015-1027. DOI: 10.1146/annurev-biochem-062917-012341. View

17.

van Velthoven C, Rando T . Stem Cell Quiescence: Dynamism, Restraint, and Cellular Idling. Cell Stem Cell. 2019; 24(2):213-225. PMC: 6413865. DOI: 10.1016/j.stem.2019.01.001. View

18.

Nilsson J, Vallbo C, Guo D, Golovleva I, Hallberg B, Henriksson R . Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun. 2001; 284(5):1155-61. DOI: 10.1006/bbrc.2001.5092. View

19.

Shi C, Yuan Y, Guo Y, Jing J, Ho T, Han X . BMP Signaling in Regulating Mesenchymal Stem Cells in Incisor Homeostasis. J Dent Res. 2019; 98(8):904-911. PMC: 6616121. DOI: 10.1177/0022034519850812. View

20.

Suzuki Y, Miura H, Tanemura A, Kobayashi K, Kondoh G, Sano S . Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia. FEBS Lett. 2002; 521(1-3):67-71. DOI: 10.1016/s0014-5793(02)02824-7. View