Differential screening of mouse skin cDNA libraries identified cDNA encoding a protein containing a Src homologous 3 (SH3) domain, a novel protein containing a SH3 domain at the carboxyl terminus, and reporting gene expression patterns during the hair growth cycle. The protein shows significant homology with an the yeast protein YHRO 16c/Ysc 84 in its amino and carboxyl terminus, suggesting that it may be a mouse homolog of the yeast protein. Therefore, we name it the Sh3 domain YSC-like 1, Sh3yl1.
SHP2, also known as PTPN11, belongs to the protein-tyrosine phosphatase(PTP) family, non-receptor class 2 subfamily. PTPs catalyze the removal of phosphate groups from tyrosine residues by the hydrolysis of phosphoric acid monoesters. They dephosphorylate EGFR, JAK2 and TYK2 kinases, promoting oncogenic transformation. SHP2 is widely expressed, with highest levels in heart, brain, and skeletal muscle. SHP2 acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. It also dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity.
Human Siglec-15 is a transmembrane glycoprotein in the Siglec family. Siglecs are type I transmembrane proteins where the NH3+-terminus is in the extracellular space and the COO--terminus is cytosolic. Each Siglec contains an N-terminal V-type immunoglobulin domain (Ig domain) which acts as the binding receptor for sialic acid. These lectins are placed into the group of I-type lectins because the lectin domain is an immunoglobulin fold. All Siglecs are extended from the cell surface by C2-type Ig domains which have no binding activity. Siglecs differ in the number of these C2-type domains. Human Siglec-15 consists of a 244 amino acid (aa) extracellular domain (ECD) with two Ig-like domains, a 21 aa transmembrane segment, and a 44 aa cytoplasmic domain. Siglec-15 function is important for osteoclast formation and TRANCE/RANK Ligand signaling in osteoclasts
Single Ig IL-1-related receptor (SIGIRR) or TIR8 is a member of Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily. Although SIGIRR/TIR8 shows the typical conserved motifs that characterize the IL-1R and Toll superfamily, it is structurally and functionally distinct from both. SIGIRR/TIR8 has only one Ig domain in its extracellular portion whereas the IL-1R family contains three Ig folds. An unusually long cytoplasmic domain is reminiscent of the structure of drosophila Toll, yet the SIGIRR peptide sequence is more closely related to IL-1RI. SIGIRR/TIR8 was mainly expressed in mouse and human epithelial tissues such as kidney, lung and gut. Resting and activated T and B lymphocytes and monocytes-macrophages expressed little or no SIGIRR/TIR8, with the exception of the mouse GG2EE macrophage line. Inflammation is enhanced in SIGIRR-deficient mice. SIGIRR negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge.
Siglecs (sialic acid binding Ig-like lectins) are I-type lectins that belong to the immunoglobulin superfamily. They are characterized by an N-terminal Ig-like V-type domain which mediates sialic acid binding, followed by a varying number of Ig-like C2-type domains. Siglecs 5-11 constitute the CD33/Siglec-3 related group, and are differentially expressed in the hematopoietic system. Siglec-G is the apparent ortholog of human Siglec-10. We describe here a novel member of the siglec protein family that shares a similar structure including five Ig-like domains, a transmembrane domain, and a cytoplasmic tail containing two ITIM-signaling motifs. Siglec-10 was identified through database mining of an asthmatic eosinophil EST library. Siglec-10 binds sialated proteins and lipids in alpha 2,3 or alpha 2,6 linkage and shows a preference for GT1b gangliosides. This binding can be modulated by cis interactions of Siglec-10 with sialated molecules expressed on the same cell. When tyrosine phosphorylated, the cytoplasmic ITIMs interact with phosphatases SHP-1 and SHP-2 to propagate inhibitory signals. The Siglec-10-VAP-1 interaction seems to mediate lymphocyte adhesion to endothelium and has the potential to modify the inflammatory microenvironment via the enzymatic end products.
CD22 is a member of the immunoglobulin superfamily, SIGLEC family of lectins. It is first expressed in the cytoplasm of pro-B and pre-B cells, and on the surface as B cells mature to become IgD+. CD22 serves as an adhesion receptor for sialic acid-bearing ligands expressed on erythrocytes and all leukocyte classes. In addition to its potential role as a mediator of intercellular interactions, signal transduction through CD22 can activate B cells and modulate antigen receptor signaling in vitro. The phenotype of CD22-deficient mice suggests that CD22 is primarily involved in the generation of mature B cells within the bone marrow, blood, and marginal zones of lymphoid tissues. CD22 recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 (SHP-1) to immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and inhibits B-cell receptor (BCR)-induced Ca2+ signaling on normal B cells. As an inhibitory coreceptor of the B-cell receptor (BCR), CD22 plays a critical role in establishing signalling thresholds for B-cell activation. Like other coreceptors, the ability of CD22 to modulate B-cell signalling is critically dependent upon its proximity to the BCR, and this in turn is governed by the binding of its extracellular domain to alpha2,6-linked sialic acid ligands. However, genetic studies in mice reveal that some CD22 functions are regulated by ligand binding, whereas other functions are ligand-independent and may only require expression of an intact CD22 cytoplasmic domain at the B-cell surface.
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