CD24: A Rheostat That Modulates Cell Surface Receptor Signaling of Diverse Receptors

CD24 (also called Heat Stable Antigen or nectadrin) is expressed on many cell types (Fang et al., 2010), and its expression is dynamically regulated during cellular differentiation (Ayre et al., 2016). CD24 was first described for its role in blocking B lymphocyte (B cell) development. Transgenic mice overexpressing CD24 and CD24 knockout mice exhibit a loss of immature B cells via their increased apoptosis (Hough et al., 1996; Nielsen et al., 1997) demonstrating that altering CD24 expression has serious repercussions in these cells. Additionally, antibody (Ab)-mediated engagement of CD24 induces apoptosis or suppresses proliferation of B cells, depending on their developmental stage (Chappel et al., 1996). CD24 also mediates homeostatic proliferation in T cells (Li et al., 2004), and can negatively regulate inflammation by inhibiting dendritic cell (DC) activation (Chen et al., 2009). CD24 also acts outside the immune system. It supports the differentiation of immature preadipocytes into adipocytes (Rodeheffer et al., 2008; Fairbridge et al., 2015; Smith et al., 2015) and is a positive regulator of cerebellar neurite outgrowth, but a negative regulator for dorsal root ganglion neurogenesis (Kleene et al., 2001). In contrast, CD24 negatively regulates corneal growth to inhibit the development of pterygium (Riau et al., 2011). CD24 can regulate both proand antiproliferative effects in cancer cells, and both increase or reduce metastasis, depending on the cancer type (Kristiansen et al., 2004; Ju et al., 2011). Finally, we and others have identified CD24 as being carried on exosomes and microvesicles (Keller et al., 2007; Ayre et al., 2015; Grigor’eva et al., 2016), where its ultimate function is unknown. CD24 has also been implicated in regulating cell stress. In a model of acetaminophen-induced liver damage, wild type mice regulated liver inflammation via CD24 and Siglec-G on DCs, whereas in CD24 knockout mice, the same challenge proved fatal (Chen et al., 2009). In addition, hypoxia in solid tumors induced CD24 expression via Hypoxia Inducible Factor-1 leading to increased tumor cell survival (Thomas et al., 2012). Finally, CD24 has been shown to regulate angiogenesis through Heat Shock Protein 90 andmodulation of the STAT3/VEGF pathway (Wang et al., 2016). Therefore, CD24 is also important for modulating the sensitivity or cellular response to extracellular stresses. CD24 is a glycophosphatidylinositol (GPI)-anchored protein, possessing no intracellular signaling domains (Kay et al., 1991). However, several signal transduction proteins are associated with CD24 activity. The best-described are the Src-family protein tyrosine kinases Lyn, Fyn, Fgr,