Encyclopedia of Signaling Molecules

Living Edition
| Editors: Sangdun Choi

Src-Like Adapter Protein (SLAP)

  • Sausan A. Moharram
  • Lars Rönnstrand
  • Julhash U. KaziEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-1-4614-6438-9_101668-1


Mitogenic Signaling Ligand Stimulation Stem Cell Factor Receptor Spleen Tyrosine Kinase Multiple Signaling Cascade 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Historical Background

Src-like adaptor protein (SLAP) is a 34 kDa protein which was initially identified in a yeast two-hybrid screen using the cytoplasmic domain of a receptor tyrosine kinase EPHA2 (Pandey et al. 1995). SLAP is an adapter protein which shares several structural features with SRC (Fig. 1). SLAP is expressed in a wide range of tissues and modulates signaling downstream of cell surface receptors. SLAP expression is not essential in embryonal development, as SLAP knockout mice did not display any critical physical abnormality and appeared to be healthy (Sosinowski et al. 2001). In adult mice, SLAP deficiency results in the higher T-cell receptor (TCR) signaling (Friend et al. 2013) and enhances the in vitro proliferation of osteoclast precursors (derived form of bone marrow macrophages) (Kim et al. 2010). Therefore, SLAP plays a role in controlling signaling downstream of receptors.
Fig. 1

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

SLAP Gene and Protein

SLAP is located on human chromosome 8q22.3 and contains seven exons and six introns (Pandey et al. 1995). The human SLAP gene encodes five splice variants. Three variants carry all intact domains (Fig. 2), while the other two variants lack at least one functional domain (Kazi et al. 2015). SLAP is expressed in a variety of tissues including spleen, lung, thymus, lymph nodes, and liver (Kazi et al. 2015). Spleen B-cells and T-cells display a moderate level of SLAP expression, suggesting a role of SLAP in B-cell and T-cell function (Sosinowski et al. 2000). SLAP has a comparatively short N-terminal uncharacterized region followed by a SRC homology 3 (SH3) domain, a SRC homology 2 (SH2) domain, and a C-terminal uncharacterized region (Fig. 2). The C-terminal uncharacterized region plays a role in dimerization of SLAP. The SH3 domain binds a proline-rich sequence motifs and mediates protein-protein interactions and the SH2 domain is well known as phosphotyrosine-binding domain. Therefore, after dimerization through the C-terminal region (Tang et al. 1999), SLAP can form a multi-protein complex through its SH2 and SH3 domains.
Fig. 2

Different SLAP isoforms. The SLAP gene is expressed as multiple transcription variants encoding several SLAP isoforms

SLAP Interacting Proteins

A variety of proteins including cell surface receptors, membrane-bound non-receptor proteins, and cytosolic proteins bind with SLAP. Since a wide range of tissues express SLAP, it is likely that SLAP regulates multiple signaling cascades through interaction with various signaling molecules. SLAP has a myristoylated site near the N-terminus (G2), and thus it localizes to the cell surface where it interacts with several receptors including B-cell receptors (BCR), the T-cell receptors (TCR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), FMS-like tyrosine kinase-3 (FLT3), EPH receptor A2 (EPHA2), and EPOR (Pandey et al. 1995; Roche et al. 1998; Tang et al. 1999; Manes et al. 2000; Lebigot et al. 2003; Kazi and Rönnstrand 2012; Kazi et al. 2014). Moreover, it has been shown that SLAP has a role in activation and maturation of monocyte and dendritic cells through downregulation of granulocyte macrophage colony-stimulating factor receptor (GM-CSFR) (Liontos et al. 2011). Besides receptors, SLAP binds to several intracellular kinases such as SYK, ZAP70 and LCK, the ubiquitin E3 ligase CBL, the guanine nucleotide exchange factor VAV1, and the SH2 domain-containing leukocyte protein SLP76 (Tang et al. 1999; Manes et al. 2000; Sosinowski et al. 2000; Hiragun et al. 2006; Park et al. 2009). Thus, SLAP plays important roles through the interaction of different types of proteins.

SLAP-Mediated Regulation of Cell Signaling

SLAP regulates multiple signaling cascades through interaction with cell surface receptors or with downstream signaling proteins. Upon TCR activation, several TCR signaling components such as ZAP70, SYK, LAT, CD3ζ, CBL, VAV1, and SLP76 interact with SLAP (Tang et al. 1999; Sosinowski et al. 2000). SLAP mainly associates with tyrosine phosphorylate signaling proteins through its SH2 domain. However, SLAP associates with CBL through its C-terminal hydrophobic region, allowing SLAP to recruit the ubiquitin machinery to tyrosine-phosphorylated signaling proteins (Fig. 3). In this way SLAP directs signaling proteins to ubiquitination-mediated degradation and therefore negatively regulates mitogenic signaling (Myers et al. 2005; Ersek et al. 2012). In BCR signaling, SLAP associates with the BCR complex as well as with spleen tyrosine kinase SYK (Fig. 3). SLAP expression is required for maintaining BCR complex levels (Dragone et al. 2006b) suggesting that SLAP expression modulates the stability of BCR complexes which is mediated through recruitment of CBL to the BCR complex (Dragone et al. 2006a). Type III receptor tyrosine kinases, PDGFR, CSF1R, FLT3, and KIT, have been demonstrated to interact with SLAP upon ligand stimulation (Kazi et al. 2015). SLAP binds to the PDGFRB through pY579 and pY581, which overlap with the SRC-binding site (Roche et al. 1998) and thus negatively regulates mitogenic signaling by competing with SRC. Similar to PDGFRB, SLAP associates with wild-type KIT in response to ligand stimulation leading to enhanced ubiquitination-directed degradation and therefore negatively regulates KIT downstream signaling (Kazi et al. 2014). However, it is unable to block mitogenic signaling mediated by an oncogenic KIT mutant (KIT/D816V). Although association of SLAP with ligand-stimulated FLT3 results in ubiquitination-mediated degradation of the receptor, it enhances FLT3 downstream signaling through an unknown mechanism (Kazi and Rönnstrand 2012). Collectively, current studies suggest that SLAP plays differential roles in signaling through different RTKs.
Fig. 3

The role of SLAP in TCR, BCR, and RTK downstream signaling. Upon activation, SLAP binds to the tyrosine-phosphorylated receptor or to components of its complex. In TCR signaling, dimerized SLAP binds to TCRζ, ZAP70, SLP-76, and LAT through the SLAP-SH2 domain. SLAP recruits CBL through its C-terminal hydrophobic region and thereby negatively regulates TCR signaling. Similar to the TCR signaling, SLAP binds to the activated BCR complex and recruits CBL. SLAP also interacts with SYK, another component of BCR signaling. SLAP interacts with ligand-stimulated RTKs and enhances ubiquitination-mediated degradation of the receptors


The adapter protein SLAP plays crucial roles in regulating receptor turnover by recruiting ubiquitin E3 ligases to the receptors. Therefore, SLAP is mainly involved in negative regulation of signaling downstream of receptors. However, there is also evidence that SLAP can enhance receptor downstream signaling, although the mechanism of this regulation has not been understood well. Our current knowledge about SLAP-mediated regulation is limited to mitogenesis, and future studies should address the role of SLAP in the regulation of different biological process including intracellular trafficking, cell cycle progression, and metabolism.


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© Springer Science+Business Media LLC 2016

Authors and Affiliations

  • Sausan A. Moharram
    • 1
  • Lars Rönnstrand
    • 1
  • Julhash U. Kazi
    • 1
    Email author
  1. 1.Division of Translational Cancer Research, Department of Laboratory MedicineLund UniversityLundSweden