Nuclear VANGL2 Inhibits Lactogenic Differentiation

Author:

Rubio Stefany12,Molinuevo Rut12,Sanz-Gomez Natalia3ORCID,Zomorrodinia Talieh12ORCID,Cockrum Chad S.2,Luong Elina2,Rivas Lucia2,Cadle Kora2,Menendez Julien12,Hinck Lindsay123

Affiliation:

1. Institute for the Biology of Stem Cells, University of California, Santa Cruz, CA 95064, USA

2. Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, CA 95064, USA

3. Department of Cancer Biology, Institute for Biomedical Research “Alberto Sols”, 28029 Madrid, Spain

Abstract

Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, transmembrane PCP proteins are trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in the HCC1569 breast cancer cell line, and in undifferentiated, but not differentiated, HC11 cells that serve as a model for mammary lactogenic differentiation. The loss of Vangl2 function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate recruitment of VANGL2 to specific DNA binding motifs, including one in the Stat5a promoter. Knockdown (KD) of Vangl2 in HC11 cells and primary mammary organoids results in upregulation of Stat5a, Ccnd1 and Csn2, larger acini and organoids, and precocious differentiation; phenotypes are rescued by overexpression of Vangl2, but not Vangl2ΔNLS. Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.

Funder

UCSC Institute for the Biology of Stem Cells and CIRM Shared Stem Cell Facilities

CIRM Major Facilities

National Institutes of Health

National Institutes of Health: Eunice Kennedy Shriver National Institute of Child Health and Human Development

California Institute of Regenerative Medicine

Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program

Spanish association against cancer AECC

IMSD

Publisher

MDPI AG

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