NR4A3 and Smad2

TFClass 2.1.4.0.3,  TFClass 7.1.1.1.2

NR4A3 (NOR1) is well known to act as a tumor suppressor in acute myeloid leukemia, and it was published before to inhibit proliferation of breast, gastric and lung cancer cells. The focus of a recent study was to elucidate the molecular mechanisms of NR4A3 action in prostate cancer (PCa) cells. NR4A3 expression in PCa has been demonstrated to be significantly up-regulated by MT-2 (TMPRSS6), a transmembrane serine protease, via iron metabolism, which contributed “to inhibit PCa tumorigenesis and metastasis” (Lin, H.Y. et al., 2022. Oncogene, 41:2833–2845).
NR4A3 has been shown to promote TGF-beta-induced SMAD2 phosphorylation and nuclear translocation, as well as up-regulation of SMAD2-target genes p21 and PAI-1, and this contributes significantly to inhibit PCa malignant cell growth. Moreover, NR4A3 has been observed in the same protein complex with SMAD2 on the SMAD-binding elements (SBE) in p21 and PAI-1 promoters.
This publication suggests a cooperation of NR4A3 and SMAD2 and their involvement in suppression of PCa tumor growth and metastasis. NR4A3 is shown to be a “contextual factor” to alter TGF-beta/SMAD pathway from tumor promotion to tumor suppression specifically in PCa under induction by iron (Lin, H.Y. et al., 2022. Oncogene, 41:2833–2845).

NR4A3 belongs to a family of NGFI-B-related receptors (NR4), which is a part of the big class of Nuclear receptors with C4 zinc fingers (Wingender at al., 2018; TFClass link). SMAD2 belongs to a subfamily of Regulatory Smads (R-Smad) within the family of SMAD factors. SMAD factors together with NF-1 factors constitute a superclass of TFs with a specific type of DNA-binding domain known as “beta-Hairpin exposed by an alpha/beta-scaffold” (Wingender at al., 2018; TFClass link). 

In the HumanPSD database NR4A3 is documented for its role in at least ten different tumors, among them are adenocarcinoma, chondrosarcoma, breast neoplasms, acute myeloid leukemia, and others.
In this publication, the NR4A3 role in PCa has been studied (Lin, H.Y. et al., 2022. Oncogene, 41:2833–2845). A disease similarity map for prostatic neoplasms (prostate cancer, PCa) is shown on the image aside and can be viewed in full-screen resolution here.

Expression of NR4A3 (NOR1) protein varies significantly between the organs and tissues investigated. The highest expression level is observed in seminal vesicles followed by approximately 2-fold lower expression in adrenal, heart, ovary, skeletal muscle, and further down to the neglectable expression in lymphocytes, monocytes and dendritic cells (HumanPSD database, Human Protein Atlas v20).

Transcription of the NR4A3 gene is known to be regulated by the following TFs: CREB, E12, E2A, HIF-1alpha, RUNX1, STAT3. Translation of NR4A3 mRNA is regulated by several miRNAs binding to its 3’-UTR (TRANSFAC database).

NR4A3 is known to bind to its specific site in the promoter of the A2M (alpha-2-macroglobulin) gene and up-regulates its transcription. Alpha-2-macroglobulin plays a role in the regulation of cell proliferation.

In TRANSFAC, there is one positional weight matrix for NR4A3 (TRANSFAC database).

Protein-protein interactions of NR4A3 with more than 40 different proteins are documented. Among interaction partners for NR4A3 are metabolic enzymes, cell cycle regulatory proteins, ubiquitin protein ligases involved in apoptosis, several keratin-associated proteins specific for signalling events in skin cells, and others (TRANSPATH database).

Lin, H.Y. et al., 2022. Matriptase-2/NR4A3 axis switches TGF-β action toward suppression of prostate cancer cell invasion, tumor growth, and metastasis. Oncogene 41, 2833–2845. PMID: 35418692

Wingender E. et al., 2018. TFClass: expanding the classification of human transcription factors to their mammalian orthologs. Nucleic Acids Res. 46, D343-D347. PMID: 29087517