Product Sheet CG1543
Description
BACKGROUND Src Homology 2 Domain–Containing Inositol 5-Phosphatase 1 (SHIP-1) is an inositol polyphosphate 5-phosphatase that has been identified by its association with the adapter protein Shc after stimulation of hematopoietic cells by a variety of hematopoietic growth factors. Expression of this protein is restricted to hematopoietic cells where its movement from the cytosol to the plasma membrane is mediated by tyrosine phosphorylation.1 It has SH2 domain at the amino terminus, an inositol polyphosphate 5-phosphatase domain in the central region, two consensus sequences for interacting with phosphotyrosine binding domains (ie NPXY) and proline-rich regions at the carboxy terminus. Alternate transcriptional splice variants, encoding different isoforms of SHIP, have been characterized.2
SHIP-1 is a negative regulator in a variety of cytokine, immunoreceptor, and growth factor signaling pathways. SHIP-1 has important functions in T cells, B cells, mast cells, basophils, and neutrophils. The phosphoinositide 3-kinase (PI3K) pathway is critical in many biologic processes, including cell proliferation, apoptosis, and migration. Activated PI3K catalyzes the formation of the lipid product phosphotidylinositol-3,4,5-trisphosphate (PIP3), which mediates downstream responses. As one of the negative regulators in this pathway, SHIP-1 selectively hydrolyzes 5\'-phosphates from inositolphosphates and phosphoinositides phosphorylated at the D3-position of the inositol ring, ie Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3, respectively, thereby SHIP-1 controls the intracellular level of PIP3. The major mechanism of SHIP-1 has been elucidated in the interaction between SHIP-1 and the inhibitory receptor Fc-gamma-RIIB of B lymphocytes. On B-cell antigen receptor–Fc-gamma-RIIB coligation, SHIP-1 is recruited to the immunoreceptor tyrosine–based inhibitory motif domain of the receptor. After localizing to the cell membrane, SHIP-1 dephosphorylates PIP3 to PI-3,4-bisphosphate, effectively reducing or terminating the downstream signaling of the PI3K pathway.3
Evidence for implicating SHIP-1 in the down-regulation of cytokine receptor signal transduction comes from the intriguing phenotype of the SHIP-1 knockout mouse which showed increased numbers of granulocyte-macrophage (GM) progenitors in bone marrow and spleen, an extensive infiltration of lungs with macrophages and a hyperresponsiveness to IL-3, SCF and colony-stimulating factors, ie GM-CSF and CSF-1.4 It was demonstrated that SHIP-1 acts as a negative regulator of B-cell antigen receptor signaling. It mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. It also acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. It regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Moreover, SHIP-1 is involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity. It was shown that SHIP-1 is a key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Additionally, it modulates FCGR3/CD16-mediated cytotoxicity in NK cells. And it participated in regulation of the activin/TGF-beta-induced apoptosis through its Smad-dependent expression.5
SHIP-1 is a negative regulator in a variety of cytokine, immunoreceptor, and growth factor signaling pathways. SHIP-1 has important functions in T cells, B cells, mast cells, basophils, and neutrophils. The phosphoinositide 3-kinase (PI3K) pathway is critical in many biologic processes, including cell proliferation, apoptosis, and migration. Activated PI3K catalyzes the formation of the lipid product phosphotidylinositol-3,4,5-trisphosphate (PIP3), which mediates downstream responses. As one of the negative regulators in this pathway, SHIP-1 selectively hydrolyzes 5\'-phosphates from inositolphosphates and phosphoinositides phosphorylated at the D3-position of the inositol ring, ie Ins(1,3,4,5)P4 and PtdIns(3,4,5)P3, respectively, thereby SHIP-1 controls the intracellular level of PIP3. The major mechanism of SHIP-1 has been elucidated in the interaction between SHIP-1 and the inhibitory receptor Fc-gamma-RIIB of B lymphocytes. On B-cell antigen receptor–Fc-gamma-RIIB coligation, SHIP-1 is recruited to the immunoreceptor tyrosine–based inhibitory motif domain of the receptor. After localizing to the cell membrane, SHIP-1 dephosphorylates PIP3 to PI-3,4-bisphosphate, effectively reducing or terminating the downstream signaling of the PI3K pathway.3
Evidence for implicating SHIP-1 in the down-regulation of cytokine receptor signal transduction comes from the intriguing phenotype of the SHIP-1 knockout mouse which showed increased numbers of granulocyte-macrophage (GM) progenitors in bone marrow and spleen, an extensive infiltration of lungs with macrophages and a hyperresponsiveness to IL-3, SCF and colony-stimulating factors, ie GM-CSF and CSF-1.4 It was demonstrated that SHIP-1 acts as a negative regulator of B-cell antigen receptor signaling. It mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. It also acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. It regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Moreover, SHIP-1 is involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity. It was shown that SHIP-1 is a key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Additionally, it modulates FCGR3/CD16-mediated cytotoxicity in NK cells. And it participated in regulation of the activin/TGF-beta-induced apoptosis through its Smad-dependent expression.5
REFERENCES
1. Liu, Q. et al: J. Exp. Med. 188:1333-42, 1998
2. Liu, L. et al: Leukemia 11:181-4, 1997
3. Tridandapani, S. et al:J. Immunol. 162:1408-14, 1999
4. Huber, M. et al: Prog Biophys Mol Biol. 71:423-34, 1999
5. Kalesnikoff, J. et al: Rev Physiol Biochem Pharmacol. 149:87-103, 2003
2. Liu, L. et al: Leukemia 11:181-4, 1997
3. Tridandapani, S. et al:J. Immunol. 162:1408-14, 1999
4. Huber, M. et al: Prog Biophys Mol Biol. 71:423-34, 1999
5. Kalesnikoff, J. et al: Rev Physiol Biochem Pharmacol. 149:87-103, 2003
Products are for research use only. They are not intended for human, animal, or diagnostic applications.
(Click to Enlarge) Immunoblotting analysis of extracts from HuvEc cells, using Anti-SHIP1, C-Terminal antibody. The lane on the left was treated with the Anti-SHIP1, C-Terminal antibody. The lane on the right (negative control) was treated with both Anti-SHIP1, C-Terminal antibody and the synthesized immunogen peptide.
Details
Cat.No.: | CG1543 |
Antigen: | Synthesized peptide derived from human SHIP1 |
Isotype: | Rabbit IgG |
Species & predicted species cross- reactivity ( ): | Human, Rat, Mouse |
Applications & Suggested starting dilutions:* | WB 1:500-1:1000 IP n/d IHC n/d ICC n/d FACS n/d ELISA 1:40000 |
Predicted Molecular Weight of protein: | 133 kDa |
Specificity/Sensitivity: | Detects endogenous SHIP-1 proteins without cross-reactivity with other family members. |
Storage: | Store at -20°C, 4°C for frequent use. Avoid repeated freeze-thaw cycles. |
*Optimal working dilutions must be determined by end user.
Products
| Product | Size | CAT.# | Price | Quantity |
|---|---|---|---|---|
| Rabbit Src Homology 2 Domain-Containing Inositol 5-Phosphatase 1 Antibody: Rabbit Src Homology 2 Domain-Containing Inositol 5-Phosphatase 1 Antibody | Size: 100 ul | CAT.#: CG1543 | Price: $384.00 |