Src-Like Adapter Protein 2 (SLAP2)
SLAP2 Gene and Protein
In contrast to its close homolog SLAP, SLAP2 has not been studied deeply. A variety of proteins including cell surface receptors (B-cell receptor (BCR), T-cell receptor (TCR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), EPH receptor A2 (EPHA2), and EPOR), and non-receptor proteins (SYK, LAT ZAP70, VAV1, LCK, CBL, and SLP-76) have been reported to associate with SLAP (Pandey et al. 1995; Roche et al. 1998; Tang et al. 1999; Manes et al. 2000; Sosinowski et al. 2000; Lebigot et al. 2003; Hiragun et al. 2006; Park et al. 2009; Kazi and Rönnstrand 2012; Kazi et al. 2014). However, current studies suggest that SLAP2 associates with TCR, CBL, colony-stimulating factor 1 receptor (CSF1R), and FLT3 (Holland et al. 2001; Loreto et al. 2002; Pandey et al. 2002; Manes et al. 2006; Moharram et al. 2016). Since SLAP2 shares considerable sequence similarity with SLAP, it is likely that SLAP2 also associates with the hitherto identified SLAP-interacting proteins.
SLAP2 Negatively Regulates TCR Signaling
SLAP2 Negatively Regulates Type III Receptor Tyrosine Kinase Signaling
Type III receptor tyrosine kinase family includes the PDGFRA, PDGFRB, KIT, FLT3, and CSF-1R. Since SLAP2 is expressed in hematopoietic cell lines where many of type III receptor kinases are expressed, it might have an important role in regulating the signaling of those receptor tyrosine kinases. SLAP2 binds constitutively to the CSF-1R in bone marrow macrophages (Manes et al. 2006). There is also evidence that SLAP2 associates with ligand-stimulated FLT3 and negatively regulates FLT3 downstream signaling by stimulating ubiquitination-dependent degradation of FLT3 (Moharram et al. 2016). Expression of SLAP2 in mouse proB cells or myeloid cells expressing an oncogenic mutant of FLT3 (FLT3-ITD) resulted in decreased mitogenic signaling. Cells expressing SLAP2 displayed poor FLT3-ITD-mediated in vitro as well as in vivo transformation potential. Therefore, like with TCR signaling, SLAP2 might play a potential role in receptor tyrosine kinase signaling.
SLAP family proteins appear to be negative regulators of mitogenic signaling downstream to BCR, TCR, and type III receptor tyrosine kinases. SLAP2 plays important roles in controlling receptor signaling. The presence of SH2 and SH3 domains facilitates multiprotein complex formation, and the C-terminal uncharacterized region of SLAP2 has the ability to recruit E3-ubiquitin ligases. Therefore, SLAP2 links between signaling proteins and the ubiquitin ligase to control receptor signaling.
- Moharram SA, Chougule RA, Su X, Li T, Sun J, Zhao H, et al. Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling. Oncotarget. 2016;7:57770-82Google Scholar
- Pandey A, Ibarrola N, Kratchmarova I, Fernandez MM, Constantinescu SN, Ohara O, et al. A novel Src homology 2 domain-containing molecule, Src-like adapter protein-2 (SLAP-2), which negatively regulates T cell receptor signaling. J Biol Chem. 2002;277:19131–8. doi:10.1074/jbc.M110318200.PubMedCrossRefGoogle Scholar