Coordination of receptor signaling in multiple hematopoietic cell lineages by the adaptor protein SLP-76

Abstract

The adaptor protein SLP-76 is expressed in multiple hematopoietic lineages including T cells, platelets, and neutrophils. SLP-76 mediated signaling is dependent on its multiple protein interaction domains, as it creates a scaffold on which key signaling complexes are built. SLP-76 is critical for supporting signaling downstream of both immunoreceptors and integrins. The signaling molecules used both upstream and downstream of SLP-76 are similar among these receptors and across cell types; however, important differences exist. Appreciating how SLP-76 coordinates signal transduction across different cell and receptor types provides insights into the complex interplay of pathways critical for activation of cells of the immune system that are essential for host defense.

Figure 1.

The domains of SLP-76 regulate its function. SLP-76 contains multiple regions that dictate its localization and association with other signaling molecules (adaptors in orange and kinases in green). The amino terminus contains three tyrosines that become phosphorylated after TCR ligation and function together to regulate the activity of Itk and activation of PLCγ1. This region also contains a critical SAM domain. The proline-rich region constitutively binds Gads as well as PLCγ1 and Lck, which lie within a PRR subdomain termed P1. Serine 376 in the PRR is a target for HPK1 phosphorylation that appears to allow for the subsequent binding of 14-3-3 family members. The carboxyl terminus of SLP-76 harbors an SH2 domain that associates with phosphorylated ADAP, CD6, and HPK1. The interaction of the SH2 domain with HPK1 regulates its kinase activity.

Figure 2.

SLP-76 supported TCR and integrin signaling. (A) SLP-76 mediated signaling downstream of the TCR. TCR ligation initiates activation of Lck that phosphorylates ITAMs present on the CD3 chains of the TCR. ZAP-70 is recruited, activated, and phosphorylates LAT and SLP-76. Phosphorylated LAT associates with PLCγ1 and Gads and in doing so, recruits SLP-76 to the membrane. Phosphorylated SLP-76 associates with Vav1, Nck, and Itk, which together activate PLCγ1 and initiate Ca²⁺ flux and actin polymerization. SLP-76 also regulates the activation of Erk, PKCθ, and Rap1. Association of SLP-76 with the ADAP/SKAP55/RIAM complex promotes inside-out signaling by localizing active Rap1. Conformational changes mediated by inside-out signaling enable high affinity binding of integrins to their receptors. (B) Outside-in signaling in neutrophils. Integrin ligation activates associated Src kinases in neutrophils. Syk may be recruited to an integrin-associated ITAM-bearing receptor or may directly associate with the integrin β chain tail. Activated Syk phosphorylates SLP-76 and initiates PLCγ2 activation, leading to cytoskeletal reorganization and cellular adhesion in a LAT- and Gads-independent manner.