FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells
NKX2.1 is a master regulator of lung morphogenesis and cell specification; however, interactions of NKX2.1 with various transcription factors to regulate cell-specific gene expression and cell fate in the distal lung remain incompletely understood. FOXO1 is a key regulator of stem/progenitor cell ma...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-03-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/11/7/1122 |
| _version_ | 1827624041604710400 |
|---|---|
| author | Qian Zhong Yixin Liu Michele Ramos Correa Crystal Nicole Marconett Parviz Minoo Changgong Li David K. Ann Beiyun Zhou Zea Borok |
| author_facet | Qian Zhong Yixin Liu Michele Ramos Correa Crystal Nicole Marconett Parviz Minoo Changgong Li David K. Ann Beiyun Zhou Zea Borok |
| author_sort | Qian Zhong |
| collection | DOAJ |
| description | NKX2.1 is a master regulator of lung morphogenesis and cell specification; however, interactions of NKX2.1 with various transcription factors to regulate cell-specific gene expression and cell fate in the distal lung remain incompletely understood. FOXO1 is a key regulator of stem/progenitor cell maintenance/differentiation in several tissues but its role in the regulation of lung alveolar epithelial progenitor homeostasis has not been evaluated. We identified a novel role for FOXO1 in alveolar epithelial cell (AEC) differentiation that results in the removal of NKX2.1 from surfactant gene promoters and the subsequent loss of surfactant expression in alveolar epithelial type I-like (AT1-like) cells. We found that the FOXO1 forkhead domain potentiates a loss of surfactant gene expression through an interaction with the NKX2.1 homeodomain, disrupting NKX2.1 binding to the <i>SFTPC</i> promoter. In addition, blocking PI-3K/AKT signaling reduces phosphorylated FOXO-1 (p-FOXO1), allowing accumulated nuclear FOXO1 to interact with NKX2.1 in differentiating AEC. Inhibiting AEC differentiation in vitro with keratinocyte growth factor (KGF) maintained an AT2 cell phenotype through increased PI3K/AKT-mediated FOXO1 phosphorylation, resulting in higher levels of surfactant expression. Together these results indicate that FOXO1 plays a central role in AEC differentiation by directly binding NKX2.1 and suggests an essential role for FOXO1 in mediating AEC homeostasis. |
| first_indexed | 2024-03-09T12:00:12Z |
| format | Article |
| id | doaj.art-063563034d8e40c7be4b0862d61af9c6 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T12:00:12Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-063563034d8e40c7be4b0862d61af9c62023-11-30T23:03:47ZengMDPI AGCells2073-44092022-03-01117112210.3390/cells11071122FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial CellsQian Zhong0Yixin Liu1Michele Ramos Correa2Crystal Nicole Marconett3Parviz Minoo4Changgong Li5David K. Ann6Beiyun Zhou7Zea Borok8Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USAHastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USAHastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USAHastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USAHastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USADepartment of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USAHastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USANKX2.1 is a master regulator of lung morphogenesis and cell specification; however, interactions of NKX2.1 with various transcription factors to regulate cell-specific gene expression and cell fate in the distal lung remain incompletely understood. FOXO1 is a key regulator of stem/progenitor cell maintenance/differentiation in several tissues but its role in the regulation of lung alveolar epithelial progenitor homeostasis has not been evaluated. We identified a novel role for FOXO1 in alveolar epithelial cell (AEC) differentiation that results in the removal of NKX2.1 from surfactant gene promoters and the subsequent loss of surfactant expression in alveolar epithelial type I-like (AT1-like) cells. We found that the FOXO1 forkhead domain potentiates a loss of surfactant gene expression through an interaction with the NKX2.1 homeodomain, disrupting NKX2.1 binding to the <i>SFTPC</i> promoter. In addition, blocking PI-3K/AKT signaling reduces phosphorylated FOXO-1 (p-FOXO1), allowing accumulated nuclear FOXO1 to interact with NKX2.1 in differentiating AEC. Inhibiting AEC differentiation in vitro with keratinocyte growth factor (KGF) maintained an AT2 cell phenotype through increased PI3K/AKT-mediated FOXO1 phosphorylation, resulting in higher levels of surfactant expression. Together these results indicate that FOXO1 plays a central role in AEC differentiation by directly binding NKX2.1 and suggests an essential role for FOXO1 in mediating AEC homeostasis.https://www.mdpi.com/2073-4409/11/7/1122FOXO1-NKX2.1 interactionkeratinocyte growth factor (KGF)PI-3K/AKTalveolar epithelial celldifferentiationtranscription |
| spellingShingle | Qian Zhong Yixin Liu Michele Ramos Correa Crystal Nicole Marconett Parviz Minoo Changgong Li David K. Ann Beiyun Zhou Zea Borok FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells Cells FOXO1-NKX2.1 interaction keratinocyte growth factor (KGF) PI-3K/AKT alveolar epithelial cell differentiation transcription |
| title | FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells |
| title_full | FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells |
| title_fullStr | FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells |
| title_full_unstemmed | FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells |
| title_short | FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells |
| title_sort | foxo1 couples kgf and pi 3k akt signaling to nkx2 1 regulated differentiation of alveolar epithelial cells |
| topic | FOXO1-NKX2.1 interaction keratinocyte growth factor (KGF) PI-3K/AKT alveolar epithelial cell differentiation transcription |
| url | https://www.mdpi.com/2073-4409/11/7/1122 |
| work_keys_str_mv | AT qianzhong foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT yixinliu foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT micheleramoscorrea foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT crystalnicolemarconett foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT parvizminoo foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT changgongli foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT davidkann foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT beiyunzhou foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells AT zeaborok foxo1coupleskgfandpi3kaktsignalingtonkx21regulateddifferentiationofalveolarepithelialcells |