Shp1 function in myeloid cells

Abstract

The motheaten mouse was first described in 1975 as a model of systemic inflammation and autoimmunity, as a result of immune system dysregulation. The phenotype was later ascribed to mutations in the cytoplasmic tyrosine phosphatase Shp1. This phosphatase is expressed widely throughout the hematopoietic system and has been shown to impact a multitude of cell signaling pathways. The determination of which cell types contribute to the different aspects of the phenotype caused by global Shp1 loss or mutation and which pathways within these cell types are regulated by Shp1 is important to further our understanding of immune system regulation. In this review, we focus on the role of Shp1 in myeloid cells and how its dysregulation affects immune function, which can impact human disease.

Keywords: Ptpn6; autoimmunity; inflammation; motheaten; tyrosine phosphatase.

Figure 1.. The structure of the Ptpn6 gene encoding the Shp1 protein, showing positions of mutations and key regulatory sites.

The Ptpn6 gene is found on mouse chromosome 6 and on human chromosome 12p13. The numbering shown is based on the mouse protein produced from the hematopoietic-specific promoter 2. The mutations that give rise to the four spontaneous mouse models detailed in Table 1 are indicated by boxes. The position of the loxP sites in the Shp1 floxed mice are shown and result in deletion of exons 1–9 in the presence of Cre protein. The amino acid changes shown in red lead to reduced phosphatase function; the C453S amino acid change creates a phosphatase-dead Shp1, whereas the other three mutations are spontaneously occurring (Y208N in mice; N225K and A550V in humans). When phosphorylated, the tyrosine and serine residues shown in black have been shown to be involved in increased or decreased phosphatase function, respectively. N-SH2, N-terminal SH2; C-SH2, C-terminal SH2.

Figure 2.. The phenotype of the mev mouse.

A mev mouse and wild-type littermate at 6 wk of age, showing patchy fur and inflammation of paws and ears.

Figure 3.. The regulation of Shp1 phosphatase activity.

(A) Under basal conditions, the N-terminal SH2 domain of Shp1 forms an intramolecular interaction with the phosphatase domain, restricting access of substrates to the phosphatase active site. The C-terminal tail of Shp1 is disordered in published crystal structures and is shown here as a dotted line. Phosphorylation of serine residues (pS) in the C-terminal tail also negatively regulates Shp1. (B) Upon engagement of the SH2 domains of Shp1 by tyrosine phosphorylated (pY) ITIMs, the SH2 domains swing out of the way, allowing access to the phosphatase active site. The N-terminal SH2 domain is held out of the way by a further intramolecular interaction (red dashed lines) to stabilize the active phosphatase. Phosphorylation of tyrosine residues in the C-terminal tail contribute to phosphatase activation.

Figure 4.. Key signaling pathways regulated by Shp1 in myeloid cells.

Examples of signaling pathways impacted by Shp1 in (A) neutrophils, (B) DCs, (C) macrophages and monocytes, and (D) mast cells, as discussed in the text. Common themes in these signaling pathways include recruitment of Shp1 by ITIM-containing proteins to dampen down ITAM receptor-mediated signaling and negative regulation of signaling through TLRs and cytokine receptors by Shp1.

Figure 4.. Key signaling pathways regulated by Shp1 in myeloid cells.

Examples of signaling pathways impacted by Shp1 in (A) neutrophils, (B) DCs, (C) macrophages and monocytes, and (D) mast cells, as discussed in the text. Common themes in these signaling pathways include recruitment of Shp1 by ITIM-containing proteins to dampen down ITAM receptor-mediated signaling and negative regulation of signaling through TLRs and cytokine receptors by Shp1.