Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Src-Like Adapter Protein 2 (SLAP2)

  • Sausan A. Moharram
  • Lars Rönnstrand
  • Julhash U. Kazi
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101669

Synonyms

Historical Background

Src-like adaptor protein 2 (SLAP2) was initially identified as an inhibitory protein of antigen receptor-mediated activation of lymphocytes (Holland et al. 2001). The SLAP family of proteins consists of two members, SLAP and SLAP2. Both SLAP and SLAP2 share similar structural features with SRC (Fig. 1). SLAP2 is expressed in a wide range of tissues including bone marrow, macrophages and hematopoietic cell lines (Kazi et al. 2015). Mice with targeted deletion of either SLAP2 or both SLAP and SLAP2 have been described with a weak phenotype (Dragone et al. 2009). However, SLAP2 has been shown to play important roles in antigen receptors and receptor tyrosine kinase signaling (Kazi et al. 2015).
Src-Like Adapter Protein 2 (SLAP2), Fig. 1

SLAP, SLAP2, and SRC display similar structural features. SLAP family proteins, SLAP and SLAP2, share SRC homology 3 (SH3) and SRC homology 2 (SH2) domains with SRC. However, the kinase domain of SRC is absent in SLAP and SLAP2 and replaced by a C-terminal still uncharacterized region

SLAP2 Gene and Protein

SLAP is located on human chromosome 20q11.23 and contains nine exons. Human SLAP2 encodes two splice variants. Both variants have all intact domains and longer variant is very similar to the mouse SLAP2 (Fig. 2). SLAP2 is expressed in a variety of tissues including platelets, spleen, leukocytes, lung, thymus, bone marrow macrophages, and hematopoietic cells (Holland et al. 2001; Loreto et al. 2002; Pandey et al. 2002; Loreto and McGlade 2003; Sugihara et al. 2010). Similar to SLAP, SLAP2 has a shorter N-terminal uncharacterized region followed by a SRC homology 3 (SH3) domain, a SRC homology 2 (SH2) domain, and a C-terminal uncharacterized region, which is shorter than that of SLAP (Fig. 1). The SH3 domain is a domain that binds to proline-rich motifs, while the SH2 domain binds to phosphotyrosine residues. Therefore, SLAP2 has the ability, using both SH2 and SH3 domains, to form a multiprotein complex.
Src-Like Adapter Protein 2 (SLAP2), Fig. 2

Different SLAP2 isoforms. The SLAP2 gene is expressed as multiple transcription variants encoding the two SLAP2 isoforms

SLAP2-Interacting Proteins

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

BCR and TCR activation lead to activation of several mitogenic signaling cascades including activation of AKT, ERK, NF-κ𝜅B, and NFAT signaling. SLAP2 expression partially blocked TCR-induced NFAT activation (Holland et al. 2001). In response to the TCR activation, SLAP2 binds to CBL and ZAP70 (Loreto et al. 2002). Association with ZAP70 is mediated through the SLAP2 SH2 domain, while the C-terminal region is involved in association with CBL. Full-length SLAP2 (isoform a), but not isoform b that lacks the C-terminal CBL-associating region, is unable to block TCR signaling (Loreto and McGlade 2003). Therefore, negative regulation of NFAT signaling is partially mediated CBL-mediated ubiquitin induced degradation of ZAP70 through ZAP70-SLAP2-CBL complex. SLAP2 expression also destabilizes SYK suggesting the existence of additional mechanisms of negative regulation of TCR signaling (Loreto et al. 2002; Sugihara et al. 2010). Additionally, SLAP2 interacts with TCRζ chain in a phosphorylation-dependent manner (Pandey et al. 2002). Thus, our current knowledge suggests that SLAP2 associates with multiple TCR signaling components including TCRζ, ZAP70, and SYK through its SH2 domain and recruits the ubiquitin E3 ligase CBL, thereby limiting the stability of TCR signaling components (Fig. 3).
Src-Like Adapter Protein 2 (SLAP2), Fig. 3

The role of SLAP2 in TCR downstream signaling. Upon TCR activation, SLAP binds to tyrosine phosphorylated TCRζ, ZAP70, and SYK through the SLAP SH2 domain. SLAP2 recruits CBL through its C-terminal hydrophobic region and thereby 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.

Summary

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.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Sausan A. Moharram
    • 1
  • Lars Rönnstrand
    • 1
  • Julhash U. Kazi
    • 1
    • 2
  1. 1.Division of Translational Cancer Research, Department of Laboratory MedicineLund UniversityLundSweden
  2. 2.Laboratory of Computational Biochemistry, KN Biomedical Research InstituteBarisalBangladesh