FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells

Zhong, Qian; Liu, Yixin; Correa, Michele Ramos; Marconett, Crystal Nicole; Minoo, Parviz; Li, Changgong; Ann, David K.; Zhou, Beiyun; Borok, Zea

doi:10.3390/cells11071122

Open AccessArticle

FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells

by

Qian Zhong

¹,

Yixin Liu

^1,2,

Michele Ramos Correa

^2,3,4,5

,

Crystal Nicole Marconett

^2,3,4,5

,

Parviz Minoo

^2,6,

Changgong Li

^2,6

,

David K. Ann

⁷,

Beiyun Zhou

^1,2,3,*,† and

Zea Borok

^2,3,8,*,†

¹

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

²

Hastings Center for Pulmonary Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

³

USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

⁴

Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

⁵

Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

⁶

Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA

⁷

Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA

⁸

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, CA 92037, USA

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Cells 2022, 11(7), 1122; https://doi.org/10.3390/cells11071122

Submission received: 21 February 2022 / Revised: 21 March 2022 / Accepted: 24 March 2022 / Published: 26 March 2022

(This article belongs to the Section Cell Signaling)

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Abstract

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 SFTPC 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.

Keywords: FOXO1-NKX2.1 interaction; keratinocyte growth factor (KGF); PI-3K/AKT; alveolar epithelial cell; differentiation; transcription

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MDPI and ACS Style

Zhong, Q.; Liu, Y.; Correa, M.R.; Marconett, C.N.; Minoo, P.; Li, C.; Ann, D.K.; Zhou, B.; Borok, Z. FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells. Cells 2022, 11, 1122. https://doi.org/10.3390/cells11071122

AMA Style

Zhong Q, Liu Y, Correa MR, Marconett CN, Minoo P, Li C, Ann DK, Zhou B, Borok Z. FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells. Cells. 2022; 11(7):1122. https://doi.org/10.3390/cells11071122

Chicago/Turabian Style

Zhong, Qian, Yixin Liu, Michele Ramos Correa, Crystal Nicole Marconett, Parviz Minoo, Changgong Li, David K. Ann, Beiyun Zhou, and Zea Borok. 2022. "FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells" Cells 11, no. 7: 1122. https://doi.org/10.3390/cells11071122

APA Style

Zhong, Q., Liu, Y., Correa, M. R., Marconett, C. N., Minoo, P., Li, C., Ann, D. K., Zhou, B., & Borok, Z. (2022). FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells. Cells, 11(7), 1122. https://doi.org/10.3390/cells11071122

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FOXO1 Couples KGF and PI-3K/AKT Signaling to NKX2.1-Regulated Differentiation of Alveolar Epithelial Cells

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