RUNX1 forms a complex with FOXP3. This interaction involves the C-terminus of RUNX1 and the FOXP3 region between the forkhead domain and the leucine zipper motif (Ono et al. 2007).

RUNX1, in complex with CBFB, binds to at least two regulatory elements in the promoter of the FOXP3 gene (Kitoh et al. 2009).

The complex of FOXP3 and the RUNX1:CBFB heterodimer binds the interferon gamma (IFNG) gene promoter (Ono et al. 2007).

Binding of the RUNX1:CBFB complex to the promoter of the FOXP3 gene stimulates FOXP3 transcription (Kitoh et al. 2009).

The complex of the RUNX1:CBFB heterodimer and FOXP3 binds the promoter of the RSPO3 gene, which encodes a WNT ligand (Recouvreux et al. 2016).

The complex of CBFB and RUNX1 (AML1) controls transcription of the FOXP3 gene. FOXP3 is a transcription factor that acts as a key regulator of development and function of regulatory T lymphocytes (Tregs). Tregs are CD25+CD4+ T lymphocytes involved in suppression of aberrant immune responses seen in autoimmune diseases and allergies. FOXP3 can bind to RUNX1 and control transcriptional activity of the RUNX1:CBFB complex. RUNX1 stimulates transcription of IL2 and IFNG1 (IFN-gamma), and the expression of these two genes is repressed upon binding of FOXP3 to RUNX1. The complex of FOXP3 and RUNX1, on the other hand, stimulates transcription of cell surface markers of Tregs, such as CD25, CTLA-4 and GITR. In the absence of FOXP3, RUNX1 represses transcription of these genes (Shevach 2000, Maloy and Powrie 2001, Sakaguchi 2004, Ono et al. 2007, Kitoh et al. 2009).
The RUNX1:CBFB complex directly stimulates transcription of the CR1 gene, encoding Complement receptor type 1 (CD35) (Kim et al. 1999, Rho et al. 2002). Expression of CR1 on the surface of activated T cells contributes to generation of Tregs (Torok et al. 2015).

The RUNX1:CBFB complex directly regulates transcription of at least two components of WNT signaling. In association with its co-factor FOXP3, the RUNX1:CBFB complex stimulates transcription of the RSPO3 gene, encoding a WNT ligand that is implicated as a breast cancer oncogene (Recouvreux et al. 2016). In association with the activated estrogen receptor alpha (ESR1), the RUNX1:CBFB complex stimulates the expression of AXIN1, which functions as a regulator of WNT signaling (Stender et al. 2010).

Similar to NOTCH1, NOTCH3 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH3, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH3, NICD3, into the cytosol. NICD3 subsequently traffics to the nucleus where it acts as a transcriptional regulator. NOTCH3 expression pattern is more restricted than the expression patterns of NOTCH1 and NOTCH2, with predominant expression of NOTCH3 in vascular smooth muscle cells, lymphocytes and the nervous system (reviewed by Bellavia et al. 2008). Based on the study of Notch3 knockout mice, Notch3 is not essential for embryonic development or fertility (Krebs et al. 2003).

Germline gain-of-function NOTCH3 mutations are an underlying cause of the CADASIL syndrome - cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is characterized by degeneration and loss of vascular smooth muscle cells from the arterial wall, predisposing affected individuals to an early onset stroke (Storkebaum et al. 2011). NOTCH3 promotes survival of vascular smooth muscle cells at least in part by induction of CFLAR (c FLIP), an inhibitor of FASLG activated death receptor signaling. The mechanism of NOTCH3 mediated upregulation of CFLAR is unknown; it is independent of the NOTCH3 coactivator complex and involves an unelucidated crosstalk with the RAS/RAF/MAPK pathway (Wang et al. 2002).

In rat brain, NOTCH3 and NOTCH1 are expressed at sites of adult neurogenesis, such as the dentate gyrus (Irvin et al. 2001). NOTCH3, similar to NOTCH1, promotes differentiation of the rat adult hippocampus derived multipotent neuronal progenitors into astroglia (Tanigaki et al. 2001). NOTCH1, NOTCH2, NOTCH3, and their ligand DLL1 are expressed in neuroepithelial precursor cells in the neural tube of mouse embryos. Together, they signal to inhibit neuronal differentiation of neuroepithelial precursors. Expression of NOTCH3 in mouse neuroepithelial precursors is stimulated by growth factors BMP2, FGF2, Xenopus TGF beta5 - homologous to TGFB1, LIF, and NTF3 (Faux et al. 2001).

In mouse telencephalon, NOTCH3, similar to NOTCH1, promotes radial glia and neuronal progenitor phenotype. This can, at least in part be attributed to NOTCH mediated activation of RBPJ-dependent and HES5-dependent transcription (Dang et al. 2006).

In mouse spinal cord, Notch3 is involved in neuronal differentiation and maturation. Notch3 knockout mice have a decreased number of mature inhibitory interneurons in the spinal cord, which may be involved in chronic pain conditions (Rusanescu and Mao 2014).

NOTCH3 amplification was reported in breast cancer, where NOTCH3 promotes proliferation and survival of ERBB2 negative breast cancer cells (Yamaguchi et al. 2008), and it has also been reported in ovarian cancer (Park et al. 2006). NOTCH3 signaling is involved in TGF beta (TGFB1) signaling-induced eptihelial to mesenchimal transition (EMT) (Ohashi et al. 2011, Liu et al. 2014)

NOTCH3 indirectly promotes development of regulatory T cells (Tregs). NOTCH3 signaling activates pre-TCR-dependent and PKC-theta (PRKCQ)-dependent NF-kappaB (NFKB) activation, resulting in induction of FOXP3 expression (Barbarulo et al. 2011). Deregulated NOTCH3 and pre-TCR signaling contributes to development of leukemia and lymphoma (Bellavia et al. 2000, Bellavia et al. 2002).