Disease relevance of SIRPA

• Expression and activation of signal regulatory protein alpha on astrocytomas [1].
• Our findings indicate that proteins belonging to the SIRP family generally regulate signals defining different physiological and pathological processes [2].
• CD47-SIRPalpha may represent a potential pathway for the control of hemolytic anemia [3].
• In contrast, SIRP expression was absent or significantly reduced on the majority of myeloid blasts from patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) [4].
• Northern blot analysis and immunoprecipitation assays showed variable expression levels of endogenous SIRPalpha transcripts in nine well-characterized glioblastoma cell lines [5].

Psychiatry related information on SIRPA

• Rats subjected to eight cycles of food deprivation and refeeding (MFR group) showed significantly decreased circulating leptin levels when compared with control rats (nearly 50% decrease in leptin levels, P < 0.01) [6].

High impact information on SIRPA

• By binding SIRPalpha or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation [7].
• CD47 on normal red blood cells prevented this elimination by binding to the inhibitory receptor signal regulatory protein alpha (SIRPalpha) [3].
• A Bit-role for integrins in apoptosis [8].
• Only Triton X-100 soluble MFR-alpha was internalized from the plasma membrane [9].
• We have studied the biosynthetic transport to and internalization of MFR isoform alpha in KB-cells [9].

Biological context of SIRPA

• Given the known role of SIRPalpha in regulating cell adhesion and responses to mitogenic growth factors, the expression of SIRPalpha1 on astrocytomas may be of considerable importance in brain tumor biology, and it offers the potential of a new avenue for therapeutic intervention [1].
• Cell-cell interactions between ubiquitously expressed integrin-associated protein (CD47) and its counterreceptor signal regulatory protein (SIRPalpha) on phagocytes regulate a wide range of adhesive signaling processes, including the inhibition of phagocytosis as documented in mice [10].
• Phylogenetic divergence of CD47 interactions with human signal regulatory protein alpha reveals locus of species specificity. Implications for the binding site [10].
• Here we provide evidence for the tissue-specific glycosylation of neuronal and haematopoietic SIRP alpha [11].
• In addition, SIRPalpha1 and SIRPalpha2 competed for the same cell binding site, suggesting a common widely expressed SIRP ligand [4].

Anatomical context of SIRPA

• Screening of nine cell lines revealed clear cell surface expression of SIRPs on five cell lines, whereas Northern blotting for SIRPalpha transcripts showed mRNA present in eight of nine cell lines [1].
• Human CD47-expressing CHO cells spread rapidly on SIRPalpha-coated glass surfaces, correlating well with the spreading of primary human T cells [10].
• In contrast, CHO cells expressing mouse CD47 spread minimally and show equally weak binding to soluble human SIRPalpha [10].
• Human lymphocytes interact directly with CD47 through a novel member of the signal regulatory protein (SIRP) family [12].
• In contrast, SIRP alpha-Fc bound relatively strong to macrophages [11].

Associations of SIRPA with chemical compounds

• Signal regulatory protein (SIRP) alpha1 is an immunoglobulin superfamily transmembrane glycoprotein that is normally expressed in subsets of myeloid and neuronal cells [1].
• Results of signal transduction experiments suggested differential regulation of PMN migration by SIRP versus CD47 by phosphatidylinositol 3-kinase and tyrosine kinases, respectively [13].
• A cell-permeable peptide that contained a polyproline sequence from Shc selectively inhibited Shc/SHP-2 association and impaired Shc but not SHP-2 binding to SHPS-1 [14].
• SIRPalpha is dynamically associated with Triton-X-100-sensitive, but Brij-98-resistant, lipid microdomains, which also contain CD81 [15].
• Immunofluorescence analysis on epidermal sheets for I-A or CD86 revealed that LC maturation induced by 2,4-dinitro-1-fluorobenzene (DNFB) or by TNF-alpha was inhibited by pretreatment with an anti-SHPS-1 monoclonal antibody (mAb) or with CD47-Fc fusion protein, a ligand for SHPS-1 [16].
• IL-10R and SIRP-alpha expression were reciprocally down-regulated by CD47 and IL-10, respectively [17].
• Integrin-mediated adhesion is required for SIRPalpha phosphorylation in both cell types [18].

Physical interactions of SIRPA

• Here we report the crystal structures of the catalytic domain of SHP-1 complexed with two peptide substrates derived from SIRPalpha, a member of the signal-regulatory proteins [19].

Regulatory relationships of SIRPA

• We show that this third SIRP is a separate gene that is expressed as a protein with unique characteristics from both alpha and beta genes and suggest that this gene should be termed SIRPgamma [12].
• The ability of protein tyrosine phosphatase SHP-1 to suppress NFkappaB can be inhibited by dominant negative mutant of SIRPalpha [20].
• Immunohistochemical analyses indicated that SHPS-1 is expressed on high endothelial venule as well as macrophages in human tonsils [21].
• Signal regulatory proteins of the alpha subtype (SIRPalpha) are ubiquitous molecules of the immunoglobulin superfamily that negatively regulate protein tyrosine kinase receptor-dependent cell proliferation [22].
• Ectopic expression of NFB42 both suppressed the formation of aggresome-like structures and the phosphorylation of the translational regulator eIF2alpha induced by overproduction of SHPS-1 as well as increased the amount of mature SHPS-1 at the cell surface [23].

Other interactions of SIRPA

• We also identified CD44 as a plasma membrane protein which, like MFR, is highly expressed at the onset of fusion [24].
• Two ligands for CD47, thrombospondin and SIRPalpha, have been described [13].
• In fact, whereas SIRPalpha mRNA and CD47 mRNA were detected in all samples, the levels of SHP-1 mRNA varied among donors [25].
• Furthermore, for Shc to be phosphorylated in response to IGF-I requires that Shc must associate with SHPS-1 and this association is mediated in part by SHP-2 [14].
• Consistent with the idea that increased phosphorylation activates SIRP function, we overexpressed human SIRPalpha1 in U87MG glioblastoma cells in order to examine how SIRPalpha1 modulates EGFR signaling pathways [26].

Analytical, diagnostic and therapeutic context of SIRPA

• Affinity chromatography with OX101 mAb and peptide sequencing revealed the rat SIRP ligand to be CD47 (integrin-associated protein) [27].
• In addition, CD47-mediated adhesion of human and pig RBCs to SIRPalpha1 surfaces resists sustained forces in centrifugation (as confirmed by atomic force microscopy) but only at SIRPalpha-coating densities far above those measurable on human neutrophils, monocytes, and THP-1 macrophages [28].
• Immunoprecipitation followed by Western blotting after SDS-PAGE under nonreducing conditions suggested that several SIRP protein species may be present in PMN [13].
• Furthermore, atomic force microscopy probing of cell membranes with human SIRPalpha confirms the species-specific interactions and provides evidence of clustering and adhesion on short time scales, but it also shows surprisingly strong forces in detachment for a signaling complex [29].
• Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRPalpha on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection [30].

References