The Role of IGSF3 in Cell Adhesion, Proliferation, and Cell Migration

Kelly Schweitzer, Kevin Ni, Sean Jacobson, Irina Bronova, Evgeny Berdyshev, Russell Bowler, Irina Petrache

Research output: Contribution to journalArticle

Abstract

RATIONALE: Tetraspanins are cell membrane-spanning proteins that transduce extracellular signals and control cell adhesion via interactions with multiple molecules, including the protein immunoglobulin superfamily, member 3 (IGSF3). Exhibiting a large extracellular domain, and anchored in tetraspanin-enriched microdomains within the plasma membrane, the function of IGSF3 is unknown. OBJECTIVES: Building on our finding that IGSF3 knockdown in lung epithelial cells increases glucosylceramides, sphingolipids that are known to enhance the stability of tetraspanin complexes, we hypothesized that IGSF3 is critical for cell adhesion. Further, because we found that IGSF3 expression was consistently decreased after cigarette smoke exposure we investigated whether genomic alterations (single-nucleotide polymorphisms [SNPs]) within IGSF3 are present in chronic obstructive pulmonary disease (COPD). METHODS: To knock down IGSF3, human bronchial epithelial cells (Beas2b) were stably transfected with lentiviral IGSF3-shRNA or control short hairpin RNA and then compared, with respect to cell adhesion, with fibronectin and migration in a scratch wound assay. The role of glucosylceramides in IGSF3 function was tested with GENZ-123346, a pharmacological inhibitor of glucosylceramide synthase. IGSF3 SNPs were evaluated in COPDGene data sets. RESULTS: Cells with IGSF3 knockdown did not exhibit increased cell death; on the contrary, they had increased rates of proliferation. However, inhibition of IGSF3 expression markedly increased cell adhesion (>twofold; P < 0.01). This was associated with significantly decreased cell migration (P < 0.01) that was restored on glucosylceramide synthase inhibition. Of the 11 IGSF3 SNPs identified to associate with COPD, rs6703791, in the exon 11 coding region, consisting of a missense A-G mutation, may regulate IGSF3 expression. CONCLUSIONS: IGSF3 may be required for lung structural cell adhesion and motility by controlling the synthesis of glycosphingolipids. Loss of IGSF3, either through exposure to cigarette smoking, or through mutations, may impair functions that require cell migration, such as lung tissue repair.

Original languageEnglish (US)
Pages (from-to)S291
JournalAnnals of the American Thoracic Society
Volume15
Issue number4
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

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Cell Adhesion
Cell Movement
Immunoglobulins
Cell Proliferation
ceramide glucosyltransferase
Glucosylceramides
Single Nucleotide Polymorphism
Lung
Chronic Obstructive Pulmonary Disease
Small Interfering RNA
Tetraspanins
Epithelial Cells
Glycosphingolipids
Mutation
Sphingolipids
Fibronectins
Smoke
Tobacco Products
Exons
Membrane Proteins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

The Role of IGSF3 in Cell Adhesion, Proliferation, and Cell Migration. / Schweitzer, Kelly; Ni, Kevin; Jacobson, Sean; Bronova, Irina; Berdyshev, Evgeny; Bowler, Russell; Petrache, Irina.

In: Annals of the American Thoracic Society, Vol. 15, No. 4, 01.12.2018, p. S291.

Research output: Contribution to journalArticle

Schweitzer, Kelly ; Ni, Kevin ; Jacobson, Sean ; Bronova, Irina ; Berdyshev, Evgeny ; Bowler, Russell ; Petrache, Irina. / The Role of IGSF3 in Cell Adhesion, Proliferation, and Cell Migration. In: Annals of the American Thoracic Society. 2018 ; Vol. 15, No. 4. pp. S291.
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abstract = "RATIONALE: Tetraspanins are cell membrane-spanning proteins that transduce extracellular signals and control cell adhesion via interactions with multiple molecules, including the protein immunoglobulin superfamily, member 3 (IGSF3). Exhibiting a large extracellular domain, and anchored in tetraspanin-enriched microdomains within the plasma membrane, the function of IGSF3 is unknown. OBJECTIVES: Building on our finding that IGSF3 knockdown in lung epithelial cells increases glucosylceramides, sphingolipids that are known to enhance the stability of tetraspanin complexes, we hypothesized that IGSF3 is critical for cell adhesion. Further, because we found that IGSF3 expression was consistently decreased after cigarette smoke exposure we investigated whether genomic alterations (single-nucleotide polymorphisms [SNPs]) within IGSF3 are present in chronic obstructive pulmonary disease (COPD). METHODS: To knock down IGSF3, human bronchial epithelial cells (Beas2b) were stably transfected with lentiviral IGSF3-shRNA or control short hairpin RNA and then compared, with respect to cell adhesion, with fibronectin and migration in a scratch wound assay. The role of glucosylceramides in IGSF3 function was tested with GENZ-123346, a pharmacological inhibitor of glucosylceramide synthase. IGSF3 SNPs were evaluated in COPDGene data sets. RESULTS: Cells with IGSF3 knockdown did not exhibit increased cell death; on the contrary, they had increased rates of proliferation. However, inhibition of IGSF3 expression markedly increased cell adhesion (>twofold; P < 0.01). This was associated with significantly decreased cell migration (P < 0.01) that was restored on glucosylceramide synthase inhibition. Of the 11 IGSF3 SNPs identified to associate with COPD, rs6703791, in the exon 11 coding region, consisting of a missense A-G mutation, may regulate IGSF3 expression. CONCLUSIONS: IGSF3 may be required for lung structural cell adhesion and motility by controlling the synthesis of glycosphingolipids. Loss of IGSF3, either through exposure to cigarette smoking, or through mutations, may impair functions that require cell migration, such as lung tissue repair.",
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T1 - The Role of IGSF3 in Cell Adhesion, Proliferation, and Cell Migration

AU - Schweitzer, Kelly

AU - Ni, Kevin

AU - Jacobson, Sean

AU - Bronova, Irina

AU - Berdyshev, Evgeny

AU - Bowler, Russell

AU - Petrache, Irina

PY - 2018/12/1

Y1 - 2018/12/1

N2 - RATIONALE: Tetraspanins are cell membrane-spanning proteins that transduce extracellular signals and control cell adhesion via interactions with multiple molecules, including the protein immunoglobulin superfamily, member 3 (IGSF3). Exhibiting a large extracellular domain, and anchored in tetraspanin-enriched microdomains within the plasma membrane, the function of IGSF3 is unknown. OBJECTIVES: Building on our finding that IGSF3 knockdown in lung epithelial cells increases glucosylceramides, sphingolipids that are known to enhance the stability of tetraspanin complexes, we hypothesized that IGSF3 is critical for cell adhesion. Further, because we found that IGSF3 expression was consistently decreased after cigarette smoke exposure we investigated whether genomic alterations (single-nucleotide polymorphisms [SNPs]) within IGSF3 are present in chronic obstructive pulmonary disease (COPD). METHODS: To knock down IGSF3, human bronchial epithelial cells (Beas2b) were stably transfected with lentiviral IGSF3-shRNA or control short hairpin RNA and then compared, with respect to cell adhesion, with fibronectin and migration in a scratch wound assay. The role of glucosylceramides in IGSF3 function was tested with GENZ-123346, a pharmacological inhibitor of glucosylceramide synthase. IGSF3 SNPs were evaluated in COPDGene data sets. RESULTS: Cells with IGSF3 knockdown did not exhibit increased cell death; on the contrary, they had increased rates of proliferation. However, inhibition of IGSF3 expression markedly increased cell adhesion (>twofold; P < 0.01). This was associated with significantly decreased cell migration (P < 0.01) that was restored on glucosylceramide synthase inhibition. Of the 11 IGSF3 SNPs identified to associate with COPD, rs6703791, in the exon 11 coding region, consisting of a missense A-G mutation, may regulate IGSF3 expression. CONCLUSIONS: IGSF3 may be required for lung structural cell adhesion and motility by controlling the synthesis of glycosphingolipids. Loss of IGSF3, either through exposure to cigarette smoking, or through mutations, may impair functions that require cell migration, such as lung tissue repair.

AB - RATIONALE: Tetraspanins are cell membrane-spanning proteins that transduce extracellular signals and control cell adhesion via interactions with multiple molecules, including the protein immunoglobulin superfamily, member 3 (IGSF3). Exhibiting a large extracellular domain, and anchored in tetraspanin-enriched microdomains within the plasma membrane, the function of IGSF3 is unknown. OBJECTIVES: Building on our finding that IGSF3 knockdown in lung epithelial cells increases glucosylceramides, sphingolipids that are known to enhance the stability of tetraspanin complexes, we hypothesized that IGSF3 is critical for cell adhesion. Further, because we found that IGSF3 expression was consistently decreased after cigarette smoke exposure we investigated whether genomic alterations (single-nucleotide polymorphisms [SNPs]) within IGSF3 are present in chronic obstructive pulmonary disease (COPD). METHODS: To knock down IGSF3, human bronchial epithelial cells (Beas2b) were stably transfected with lentiviral IGSF3-shRNA or control short hairpin RNA and then compared, with respect to cell adhesion, with fibronectin and migration in a scratch wound assay. The role of glucosylceramides in IGSF3 function was tested with GENZ-123346, a pharmacological inhibitor of glucosylceramide synthase. IGSF3 SNPs were evaluated in COPDGene data sets. RESULTS: Cells with IGSF3 knockdown did not exhibit increased cell death; on the contrary, they had increased rates of proliferation. However, inhibition of IGSF3 expression markedly increased cell adhesion (>twofold; P < 0.01). This was associated with significantly decreased cell migration (P < 0.01) that was restored on glucosylceramide synthase inhibition. Of the 11 IGSF3 SNPs identified to associate with COPD, rs6703791, in the exon 11 coding region, consisting of a missense A-G mutation, may regulate IGSF3 expression. CONCLUSIONS: IGSF3 may be required for lung structural cell adhesion and motility by controlling the synthesis of glycosphingolipids. Loss of IGSF3, either through exposure to cigarette smoking, or through mutations, may impair functions that require cell migration, such as lung tissue repair.

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