Nuclear VANGL2 Inhibits Lactogenic Differentiation.

Area of Science:

• Cell Biology
• Developmental Biology
• Cancer Research

Background:

• Planar cell polarity (PCP) proteins regulate tissue morphogenesis and cell polarity.
• Transmembrane PCP proteins are endocytosed, suggesting potential intracellular roles.
• The nuclear functions of PCP proteins, particularly in transcriptional control, are largely unknown.

Purpose of the Study:

• To investigate the intracellular and potential transcriptional roles of the transmembrane PCP protein VANGL2.
• To determine if VANGL2 influences mammary gland differentiation and associated signaling pathways.

Main Methods:

• Nuclear localization of VANGL2 was assessed in breast cancer and mammary cell lines.
• VANGL2's DNA-binding capacity and nuclear localization signal were identified.
• CUT&RUN assays were performed to map VANGL2's genomic binding sites.
• Vangl2 knockdown and overexpression studies were conducted in cell lines and organoids.

Main Results:

• VANGL2 was found in the nucleus of undifferentiated mammary cells and breast cancer cells.
• Loss of Vangl2 function led to STAT5 signaling pathway upregulation.
• VANGL2 binds to DNA, including the Stat5a promoter, and its knockdown upregulates Stat5a, Ccnd1, and Csn2.
• Vangl2 knockdown induced larger acini, precocious differentiation, and phenotypes rescued by wild-type Vangl2.

Conclusions:

• Transmembrane PCP proteins, like VANGL2, can function intracellularly to regulate gene transcription.
• VANGL2 acts as a transcriptional regulator, suppressing differentiation programs in mammary cells.
• These findings establish a new paradigm for PCP proteins coordinating tissue morphogenesis via transcriptional control.