SLP76

SLP-76, or SH2 domain-containing leukocyte protein 76 kDa, is a cytosolic adaptor protein encoded by the LCP2 gene and expressed mainly in hematopoietic cells. It is a key component of T cell receptor (TCR) signaling and contributes to signaling downstream of other activating receptors in certain leukocytes.

During TCR engagement, SLP-76 is recruited to the LAT signalosome via the adaptor Gads and is phosphorylated by ZAP-70. Phosphorylated SLP-76 serves as a scaffold that recruits and coordinates other signaling molecules, including PLC-γ1, Vav family GEFs, and other kinases. This assembly promotes calcium mobilization, activation of the RAS/MAPK pathway, and cytoskeletal rearrangements essential for T cell activation, proliferation, and differentiation. SLP-76 also participates in platelet activation through GPVI signaling, illustrating a broader role in hematopoietic cell signaling.

Expression is highest in T cells, with additional roles in other leukocytes and platelets. Functional studies in mice show that loss of SLP-76 disrupts thymocyte development and impairs mature T cell responses, underlining its essential role in adaptive immunity. In humans, defects in SLP-76–mediated signaling are associated with immunodeficiency characterized by reduced T cell function and defective TCR signaling.

Structurally, SLP-76 contains an SH2 domain and multiple tyrosine-based motifs that, when phosphorylated, create docking sites for SH2-containing signaling proteins, enabling the assembly of multi-protein signaling complexes downstream of the TCR. It is encoded by the LCP2 gene and has an approximate molecular weight of 76 kDa.