Multi-functional adaptor SKAP1: regulator of integrin activation, the stop-signal, and the proliferation of T cells

Abstract

T-cell activation is a complex process involving a network of kinases and downstream molecular scaffolds or adaptors that integrate surface signals with effector functions. One key immune-specific adaptor is Src kinase-associated phosphoprotein 1 (SKAP1), which is also known as src kinase-associated protein of 55 kDa (SKAP55). This mini-review explains how SKAP1 plays multiple roles in regulating integrin activation, the "stop-signal", and the optimization of the cell cycling of proliferating T cells through interactions with various mediators, including the Polo-like kinase 1 (PLK1). Ongoing research on SKAP1 and its binding partners will likely provide important insights into the regulation of immune function and have implications for the development of new treatments for disease states such as cancer and autoimmunity.

Keywords: SKAP1; T-cells; adaptor protein; integrin activation; signalling.

Figure 1

The structure and binding sites of SKAP1. Human SKAP1 possesses an N-terminal dimerization (DM) domain, a species-specific disordered region, a pleckstrin homology (PH) domain (N107–K210), and a C-terminal SH3 domain (D294–E355) (33, 39). SKAP1 binds to ADAP via its SH3 domain and, to a lesser extent, via a SKAP1 RKxxYxxY motif that binds to an SH3C domain (41, 42). SKAP1 can form homodimers or heterodimers with related SKAP2 (SKAP-related R or SKAP-Hom) in cells mediated by residues A17 to L21 in the SKAP1 N-terminal region (43). The function of dimer formation is not known.

Figure 2

TCR induced pathways linking SKAP1 to the regulation of integrin-mediated adhesion and intracellular proliferation pathways. TCR ligation leads to the formation of the LAT signalosome (LAT and associated SLP-76, GADs, ADAP, and SKAP1). TCR (and CD28) also induces the presence of D-3 lipids, which bind and recruit SKAP1 via its PH (pleckstrin homology) domain to the plasma membrane (PM). By binding to RapL in the cytoplasm, SKAP1 acts as a chaperone or shuttle protein to transport RapL to the PM to interact with the GTP-binding protein Rap1 (see upper heavy arrow between SKAP1 and RapL where RapL is moved to the cell surface upward heavy arrow). The RapL–Rap1 complex depends on the presence of SKAP1 as shown by the observation that complex formation fails to form in skap1-/- primary T cells in response to TCR ligation. The complex at the cell surface with associated SKAP1 then binds to the αL chain of LFA-1. Concurrently, SKAP1 also binds to RIAM via the DM domain. By contrast to the αL chain, the β2 chain binds to Talin and various Kindlins in a complex that includes direct Talin binding to RIAM, Paxillin, and Vinculin (see upper right image of LFA-1). Complex formation promotes increased affinity as well as the clustering of LFA-1 for increased binding avidity in binding to ICAMs. SKAP1 also forms a dimer via its DM domain where it regulates the movement of SLP-76 micro-clusters. Whether dimerization controls the binding of RapL and RIAM is not known. In addition to mediating integrin activation, SKAP1 is phosphorylated by and binds to Polo-like kinase (PLK1) for the optimal cycling of T cells (see lower image of SKAP1 dimer). PLK1 binds to the N-terminal residue serine 31 (S31) of SKAP1 and the interaction is needed for optimal PLK1 kinase activity and cell cycling. The C-terminus of SKAP1 also binds to RasGRP1 and can negatively regulate the p21^ras-ERK pathway or in binding to GRB-2 may promote ERK activation. Whether this occurs alone or in conjunction with GRB-2 binding to LAT remains to be resolved. Solid arrows indicate direct interaction, whereas dotted arrows reflect indirect and unestablished interactions.