PDGFRβ translocates to the nucleus and regulates chromatin remodeling via TATA element-modifying factor 1

Area of Science:

• Cell Biology
• Molecular Oncology
• Signal Transduction

Background:

• Nuclear translocation of tyrosine kinase receptors is a known phenomenon.
• The role of cell surface receptors, like platelet-derived growth factor receptor beta (PDGFRβ), in nuclear functions is increasingly recognized.

Purpose of the Study:

• To investigate the nuclear localization and function of full-length PDGFRβ after ligand stimulation.
• To elucidate the molecular mechanisms and signaling pathways involved in PDGFRβ nuclear translocation and its impact on gene regulation.

Main Methods:

• Utilized cell-based assays to track PDGFRβ localization upon PDGF-BB stimulation.
• Employed techniques such as receptor dimerization assays, clathrin-mediated endocytosis inhibition, and β-importin dependency studies.
• Investigated protein-protein interactions within the nucleus using co-immunoprecipitation and analyzed chromatin remodeling complex activity.

Main Results:

• A fraction of full-length PDGFRβ translocates to the nucleus, associating with chromatin and the nuclear matrix.
• Nuclear translocation is dependent on receptor dimerization, endocytosis, β-importin, and Golgi integrity.
• Nuclear PDGFRβ forms complexes with Fer and TMF-1, leading to reduced TMF-1 binding to Brg-1 and SWI-SNF complex dissociation.
• TMF-1 knockdown impairs PDGFRβ nuclear import and up-regulates the cell cycle inhibitor CDKN1A (p21).

Conclusions:

• Nuclear PDGFRβ plays a critical role in regulating cell proliferation through chromatin remodeling.
• The nuclear PDGFRβ-TMF-1-Brg-1 axis modulates p21 expression, impacting cell cycle control.
• These findings reveal a novel non-canonical function of PDGFRβ in nuclear signaling pathways relevant to both normal and cancer cells.