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PubMed2000

Essential role for the C-terminal noncatalytic region of SHIP in FcgammaRIIB1-mediated inhibitory signaling.

The inositol phosphatase SHIP binds to the FcgammaRIIB1 receptor and plays a critical role in FcgammaRIIB1-mediated inhibition of B-cell proliferation and immunoglobulin synthesis. The molecular details of SHIP function are not fully understood. While point mutations of the signature motifs in the inositol phosphatase domain abolish SHIP's ability to inhibit calcium flux in B cells, little is known about the function of the evolutionarily conserved, putative noncatalytic regions of SHIP in vivo. In this study, through a systematic mutagenesis approach, we identified the inositol phosphatase domain of SHIP between amino acids 400 and 866. Through reconstitution of a SHIP-deficient B-cell line with wild-type and mutant forms of SHIP, we demonstrate that the catalytic domain alone is not sufficient to mediate FcgammaRIIB1/SHIP-dependent inhibition of B-cell receptor signaling. Expression of a truncation mutant of SHIP that has intact phosphatase activity but lacks the last 190 amino acids showed that the noncatalytic region in the C terminus is essential for inhibitory signaling. Mutation of two tyrosines within this C-terminal region, previously identified as important in binding to Shc, showed a reduced inhibition of calcium flux. However, studies with an Shc-deficient B-cell line indicated that Shc-SHIP complex formation is not required and that other proteins that bind these tyrosines may be important in FcgammaRIIB1/SHIP-mediated calcium inhibition. Interestingly, membrane targeting of SHIP lacking the C terminus is able to restore this inhibition, suggesting a role for the C terminus in localization or stabilization of SHIP interaction at the membrane. Taken together, these data suggest that the noncatalytic carboxyl-terminal 190 amino acids of SHIP play a critical role in SHIP function in B cells and may play a similar role in several other receptor systems where SHIP functions as a negative regulator.

Antigens, CD↗
PubMed2001

SHIP's C-terminus is essential for its hydrolysis of PIP3 and inhibition of mast cell degranulation.

The SH2-containing inositol-5'-phosphatase, SHIP, restrains bone marrow-derived mast cell (BMMC) degranulation, at least in part, by hydrolyzing phosphatidylinositol (PI)-3-kinase generated PI-3,4,5-P(3) (PIP3) to PI-3,4-P(2). To determine which domains within SHIP influence its ability to hydrolyze PIP3, bone marrow from SHIP(-/-) mice was retrovirally infected with various SHIP constructs. Introduction of wild-type SHIP into SHIP(-/-) BMMCs reverted the Steel factor (SF)-induced increases in PIP3, calcium entry, and degranulation to those observed in SHIP(+/+) BMMCs. A 5'-phosphatase dead SHIP, however, could not revert the SHIP(-/-) response, whereas a SHIP mutant in which the 2 NPXY motifs were converted to NPXFs (2NPXF) could partially revert the SHIP(-/-) response. SF stimulation of BMMCs expressing the 2NPXF, which could not bind Shc, led to the same level of mitogen-activated protein kinase (MAPK) phosphorylation as that seen in BMMCs expressing the other constructs. Surprisingly, C-terminally truncated forms of SHIP, lacking different amounts of the proline rich C-terminus, could not revert the SHIP(-/-) response at all. These results suggest that the C-terminus plays a critical role in enabling SHIP to hydrolyze PIP(3) and inhibit BMMC degranulation.

Amino Acid Motifs↗
PubMed1993

Shipping stress and social status effects on pig performance, plasma cortisol, natural killer cell activity, and leukocyte numbers.

Crossbred pigs were used to evaluate the effects of shipping stress on natural killer (NK) cell activity, leukocyte numbers, plasma cortisol, and BW changes. In the first study, pigs were bled at a commercial farm and, after shipping, resident and shipped pigs were bled again. Plasma cortisol concentrations were not different (P > .10) because of large variation in cortisol concentrations. Furthermore, NK cytotoxicity was nondetectable among all pigs. A second study showed that plasma cortisol concentration rose by approximately 2.6 ng/mL (P = .018) for each minute after pigs were aroused. In the third, more controlled study, pigs were housed in pens of three pigs each. Video recordings were made during the first 24 h pigs were grouped to identify socially dominant, intermediate, and submissive pigs. At time zero (before shipping), resident pigs and those to be shipped had similar plasma cortisol concentrations. However, after the 4-h shipping experience, shipped pigs had elevated (P < .05) plasma cortisol compared with resident control pigs. Shipped pigs lost 5.1% of their BW (P < .05) compared with resident pigs, which gained .02% of their BW. Body weight change during shipping and plasma cortisol were negatively correlated (r = -.34, P = .04), indicating pigs that had greater adrenal response to shipping also lost more weight during shipping. Shipping reduced (P < .05) NK cytotoxicity among pigs of intermediate and submissive social status compared with shipped, dominant pigs. At the end of shipping or control treatments, the correlation between NK cytotoxicity and plasma cortisol was positive (r = .35, P = .036), indicating that pigs with greater cortisol response had greater NK cytotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Effects of overexpression of the SH2-containing inositol phosphatase SHIP on proliferation and apoptosis of erythroid AS-E2 cells.

Previous studies have demonstrated that SH2-containing inositol phosphatase (SHIP) is involved in the control of B cell, myeloid cell and macrophage activation and proliferation. The goal of the present study was to examine the role of SHIP during proliferation and apoptosis in cells of the erythroid lineage. Wild-type and catalytically inactive SHIP proteins were overexpressed in the erythropoietin (EPO)-dependent cell line AS-E2. Stable overexpression of catalytically inactive SHIP decreased proliferation and resulted in prolonged activation of the extracellular signal-regulated protein kinases ERK1/2 and protein kinase B (PKB), while wild-type SHIP did not affect EPO-mediated proliferation or phosphorylation of ERK and PKB. When AS-E2 cells were EPO deprived a significant increase in apoptosis was observed in clones overexpressing wild type. Mutational analysis showed that this increase in apoptosis was independent of the enzymatic activity of SHIP. The enhanced apoptosis due to overexpression of SHIP was associated with an increase in caspase-3 and -9 activity, without a distinct effect on caspase-8 activity or mitochondrial depolarization. Moreover, in cells overexpressing SHIP apoptosis could be reduced by a caspase-3 inhibitor. These data demonstrate that in the erythroid cell line AS-E2 overexpression of catalytically inactive SHIP reduced proliferation, while overexpression of wild-type SHIP had no effect. Furthermore, overexpression of SHIP enhanced apoptosis during growth factor deprivation by inducing specific caspase cascades, which are regulated independently of the 5-phosphatase activity of SHIP.

Apoptosis↗
PubMed1999

BCR/ABL directly inhibits expression of SHIP, an SH2-containing polyinositol-5-phosphatase involved in the regulation of hematopoiesis.

The BCR/ABL oncogene causes chronic myelogenous leukemia (CML), a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and granulocyte lineage cells. The SH2-containing inositol-5-phosphatase SHIP is a 145-kDa protein which has been shown to regulate hematopoiesis in mice. Targeted disruption of the murine SHIP gene results in a myeloproliferative syndrome characterized by a dramatic increase in numbers of granulocyte-macrophage progenitor cells in the marrow and spleen. Also, hematopoietic progenitor cells from SHIP(-/-) mice are hyperresponsive to certain hematopoietic growth factors, a phenotype very similar to the effects of BCR/ABL in murine cells. In a series of BCR/ABL-transformed hematopoietic cell lines, Philadelphia chromosome (Ph)-positive cell lines, and primary cells from patients with CML, the expression of SHIP was found to be absent or substantially reduced compared to untransformed cell lines or leukemia cells lacking BCR/ABL. Ba/F3 cells in which expression of BCR/ABL was under the control of a tetracycline-inducible promoter showed rapid loss of p145 SHIP, coincident with induction of BCR/ABL expression. Also, an ABL-specific tyrosine kinase inhibitor, CGP57148B (STI571), rapidly caused reexpression of SHIP, indicating that BCR/ABL directly, but reversibly, regulates the expression of SHIP protein. The estimated half-life of SHIP protein was reduced from 18 h to less than 3 h. However, SHIP mRNA also decreased in response to BCR/ABL, suggesting that SHIP protein levels could be affected by more than one mechanism. Reexpression of SHIP in BCR/ABL-transformed Ba/F3 cells altered the biological behavior of cells in culture. The reduction of SHIP due to BCR/ABL is likely to directly contribute to the pathogenesis of CML.

Animals↗
PubMed1981

Transit factors affecting shrink, shipping fever and subsequent performance of feeder calves.

Five shipments of feeder calves (965 head hauled in 11 drop-center trailers) were shipped 1,600 km by tractor trailer from Algood, Tennessee, to Bushland, Texas, during the fall seasons of 1976, 1977 and 1978. Shrink, incidence of shipping fever and subsequent feedlot performance of these feeder calves were analyzed. There were significant differences in shrink and subsequent feedlot performance between calves shipped on different dates. In only one instance was there a significant difference in shrink between trucks of steers shipped on the same date, and this was due to a difference of in-transit time between trucks. There were no significant differences in shrink, incidence of shipping fever of feedlot performance between calves shipped in different trailer compartments, nor were there any interactions between shipping dates and trailer compartments for shrink, incidence of shipping fever and feedlot performance. The number of calves treated for shipping fever did not differ significantly among trailer compartments, but did differ among shipment dates. Significant differences in morbidity between shipping dates indicate that the incidence of shipping fever is apparently affected by environmental conditions before, during and immediately after transit. The results indicate that multiple truckloads of calves, if traveling together, can be treated as a single unit for the statistical analysis of shrink, incidence of shipping fever and feedlot performance.

Animals↗
PubMed2003

Diarrheal disease on cruise ships, 1990-2000: the impact of environmental health programs.

BACKGROUND: In 1975, the then-Center for Disease Control (CDC) established the Vessel Sanitation Program (VSP) to minimize the risk for diarrheal disease among passengers and crew aboard ships by assisting the cruise ship industry in developing and implementing comprehensive environmental health programs. OBJECTIVES: To evaluate the relationship between cruise ship sanitation scores and diarrheal disease incidence and outbreaks among cruise ship passengers. METHODS: Retrospective cohort study of ship inspection and diarrheal disease data from 1990 through 2000 from the National Center for Environmental Health, CDC database, for cruise ships entering the United States. OUTCOMES: Yearly trends in number of ships inspected, number of inspections conducted, inspection scores, and risks of failing inspections; rates of diarrheal disease among passengers, by inspection year, cruise duration, incidence of outbreaks, and passing- or failing-score status of the associated ship. RESULTS: From 1990 through 2000, inspection scores gradually increased from a median of 89 in 1990 to 93 in 2000 (p<0.001), with an associated statistically significant 21% increase in likelihood of passing. The total baseline level of diarrhea among passengers was 2.0 cases per cruise (13243/6485), or 23.6 cases per 100,000 passenger-days (13243/56129096). The latter rate declined significantly from 29.2 in 1990 to 16.3 in 2000 (p<0.0001). Diarrheal disease incidence rates among passengers sailing on ships that passed environmental inspections were significantly lower than rates among passengers sailing on ships that failed inspections (21.7 vs 30.1; RR = 1.39; 95% CI: 1.31-1.47). Diarrheal disease outbreak-related illnesses decreased from 4.2 to 3.5 per 100000 passenger-days from 1990-1995 to 1996-2000. CONCLUSIONS: Environmental sanitation inspections conducted among ships sailing into the United States appear to continue to decrease diarrheal disease rates and outbreaks among passengers.

Centers for Disease Control and Prevention, U.S.↗
PubMed1999

CD28 stimulates tyrosine phosphorylation, cellular redistribution and catalytic activity of the inositol lipid 5-phosphatase SHIP.

The D-3 phosphoinositide lipids phosphatidylinositol 3,4, 5-trisphophate [PtdIns(3,4,5)P(3)] and phosphatidylinositol 3, 4-bisphosphate [PtdIns(3,4)P(2)] represent upstream components of a major signaling pathway that is strongly activated by the T cell costimulatory molecule CD28. A major route for degradation of PtdIns(3,4,5)P(3) (and hence, regulation of PtdIns(3,4,5)P(3)-driven effector pathways), involves its conversion to PtdIns(3,4)P(2) by the 145-kDa SH2-containing inositol (poly)phosphate 5-phosphatase (SHIP). In this study, we demonstrate using the murine T cell hybridoma DC27.1, that SHIP is strongly tyrosine phosphorylated after ligation of CD28 by either mAb or the natural ligand B7.1. Ligation of CD3 also stimulates SHIP tyrosine phosphorylation and an additive effect on tyrosine phosphorylation of SHIP is observed when both CD3 and CD28 are ligated. The tyrosine phosphorylation of SHIP in response to CD28 ligation correlates with a marked redistribution of SHIP from the cytosol to the plasma membrane, as well as an increase in the in vitro 5-phosphatase activity associated with SHIP immunoprecipitates derived from CD28-stimulated cells. However, we have been unable to detect a direct association between CD28 and SHIP, so the mechanisms by which CD28 exerts the observed effects on SHIP remain unclear. This is the first demonstration that SHIP is a biochemical target for CD28 and suggests that SHIP may be involved in the regulation of T cell activation.

Animals↗
PubMed1998

The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation.

To clarify the role that the src homology 2-containing inositol phosphatase (SHIP) plays in mast cell degranulation, the gene for SHIP was disrupted by homologous recombination in embryonic stem cells. Bone-marrow-derived mast cells from SHIP+/+, +/-, and -/- F2 littermates were compared. SHIP-/- mast cells were found to be far more prone to degranulation, after the crosslinking of IgE preloaded cells, than SHIP+/- or +/+ cells. Intriguingly, IgE alone also stimulated massive degranulation in SHIP-/- but not in +/+ mast cells. This degranulation with IgE alone, which may be due to low levels of IgE aggregates, correlated with a higher and more sustained intracellular calcium level than that observed with SHIP+/+ cells and was dependent upon the entry of extracellular calcium. Immunoprecipitation studies revealed that the addition of IgE alone to normal mast cells stimulates multiple cascades, which are prevented from progressing to degranulation by SHIP. PI 3-kinase inhibitor studies suggested that IgE-induced activation of PI 3-kinase is upstream of the entry of extracellular calcium and that SHIP restricts this entry by hydrolyzing phosphatidylinositol 3,4, 5-trisphosphate. These results show the critical role that SHIP plays in setting the threshold for degranulation and that SHIP directly modulates a "positive-acting" receptor.

Androstadienes↗
PubMed2002

SHIP negatively regulates IgE + antigen-induced IL-6 production in mast cells by inhibiting NF-kappa B activity.

We demonstrate in this study that IgE + Ag-induced proinflammatory cytokine production is substantially higher in Src homology-2-containing inositol 5'-phosphatase (SHIP)(-/-) than in SHIP(+/+) bone marrow-derived mast cells (BMMCs). Focusing on IL-6, we found that the repression of IL-6 mRNA and protein production in SHIP(+/+) BMMCs requires the enzymatic activity of SHIP, because SHIP(-/-) BMMCs expressing wild-type, but not phosphatase-deficient (D675G), SHIP revert the IgE + Ag-induced increase in IL-6 mRNA and protein down to levels seen in SHIP(+/+) BMMCs. Comparing the activation of various signaling pathways to determine which ones might be responsible for the elevated IL-6 production in SHIP(-/-) BMMCs, we found the phosphatidylinositol 3-kinase/protein kinase B (PKB), extracellular signal-related kinase (Erk), p38, c-Jun N-terminal kinase, and protein kinase C (PKC) pathways are all elevated in IgE + Ag-induced SHIP(-/-) cells. Moreover, inhibitor studies suggested that all these pathways play an essential role in IL-6 production. Looking downstream, we found that IgE + Ag-induced IL-6 production is dependent on the activity of NF-kappa B and that I kappa B phosphorylation/degradation and NF-kappa B translocation, DNA binding and transactivation are much higher in SHIP(-/-) BMMCs. Interestingly, using various pathway inhibitors, it appears that the phosphatidylinositol 3-kinase/PKB and PKC pathways elevate IL-6 mRNA synthesis, at least in part, by enhancing the phosphorylation of I kappa B and NF-kappa B DNA binding while the Erk and p38 pathways enhance IL-6 mRNA synthesis by increasing the transactivation potential of NF-kappa B. Taken together, our data are consistent with a model in which SHIP negatively regulates NF-kappa B activity and IL-6 synthesis by reducing IgE + Ag-induced phosphatidylinositol-3,4,5-trisphosphate levels and thus PKB, PKC, Erk, and p38 activation.

Animals↗
PubMed1997

The human SHIP gene is differentially expressed in cell lineages of the bone marrow and blood.

The macrophage colony-stimulating factor receptor and several other hematopoietic growth factor receptors induce the tyrosine phosphorylation of a 145- to 150-kD protein in murine cells. We have previously cloned a cDNA for the murine 150-kD protein, SHIP, and found that it encodes a unique signaling intermediate that binds the SHC PTB domain through at least one tyrosine phosphorylated (NPXY) site in the carboxyl-terminal region. SHIP also contains several potential SH3 domain-binding sites, an SH2 domain for binding other tyrosine phosphorylated proteins, and an enzymatic activity that removes the phosphate from the 5 position of phosphatidylinositol 3,4,5-phosphate or from inositol 1,3,4,5-phosphate. SHIP has a negative effect on cell growth and therefore loss or modification may have profound effects on hematopoietic cell development. In this study, we have cloned a cDNA for human SHIP and examined mRNA and protein expression of SHIP and related species in bone marrow and blood cells. Flow cytometry indicates that at least 74% of immature CD34+ cells express SHIP cross-reacting protein species, whereas within the more mature population of CD33+ cells, only 10% of cells have similar expression. The majority of T cells react positively with the anti-SHIP antibodies, but significantly fewer B cells are positive. Immunoblotting detects up to seven different cross-reacting SHIP species, with peripheral blood mononuclear cells exhibiting primarily a 100-kD protein and a CD34+ acute myeloblastic leukemia expressing mainly 130-kD and 145-kD forms of SHIP. Overall, these results indicate that there is an enormous diversity in the size of SHIP or SHIP-related mRNA and protein species. Furthermore, the expression of these protein species changes according to both the developmental stage and differentiated lineage of the mature blood cell.

Amino Acid Sequence↗
PubMedDate not supplied

A review of outbreaks of waterborne disease associated with ships: evidence for risk management.

OBJECTIVE: The organization of water supply to and on ships differs considerably from that of water supply on land. Risks of contamination can arise from source water at the port or during loading, storage, or distribution on the ship. The purpose of this article is to review documented outbreaks of waterborne diseases associated with passenger, cargo, fishing, and naval ships to identify contributing factors so that similar outbreaks can be prevented in the future. METHODS: The authors reviewed 21 reported outbreaks of waterborne diseases associated with ships. For each outbreak, data on pathogens/toxins, type of ship, factors contributing to outbreaks, mortality and morbidity, and remedial action are presented. RESULTS: The findings of this review show that the majority of reported outbreaks were associated with passenger ships and that more than 6,400 people were affected. Waterborne outbreaks due to Enterotoxigenic Escherichia coli, noroviruses, Salmonella spp, Shigella sp, Cryptosporidium sp, and Giardia lamblia occurred on ships. Enterotoxigenic E. coli was the pathogen most frequently associated with outbreaks. One outbreak of chemical water poisoning also occurred on a ship. Risk factors included contaminated port water, inadequate treatment, improper loading techniques, poor design and maintenance of storage tanks, ingress of contamination during repair and maintenance, cross-connections, back siphonage, and insufficient residual disinfectant. CONCLUSIONS: Waterborne disease outbreaks on ships can be prevented. The factors contributing to outbreaks emphasize the need for hygienic handling of water along the supply chain from source to consumption. A comprehensive approach to water safety on ships is essential. This may be achieved by the adoption of Water Safety Plans that cover design, construction, operation, and routine inspection and maintenance.

Communicable Disease Control↗
PubMed1997

Activation-induced bi-dentate interaction of SHIP and Shc in B lymphocytes.

SHIP is a SH2 domain-containing inositol polyphosphatase that is selectively tyrosine phosphorylated and associated with the adapter protein Shc in B lymphocytes upon co-crosslinking surface immunoglobulin and Fc gamma RIIB1. We previously observed that this stimulation condition is associated with a reduction in the interaction of Grb2 with phosphorylated Shc, an enhanced interaction of Shc with SHIP, and a block in the Ras signaling pathway. We proposed that the SH2 domain of SHIP competes with Grb2 in binding to phospho-Shc, resulting in a block in Ras signaling. To test this model, we examined the mode of SHIP-Shc interaction. Using recombinant Shc and SHIP interaction domains and purified Shc and SHIP phosphopeptides, we show that the interaction is bi-dentate such that the SH2 domain of SHIP recognizes phosphorylated Y317 and doubly-phosphorylated Y239/Y240 of Shc and the Shc PTB domain recognizes phosphorylated NPxpY motifs within SHIP. We observed no role for the Shc SH2 domain in the interaction. These findings are consistent with our earlier model that SHIP and Grb2 compete for binding to phospho-Shc and support the notion that, in addition to the hydrolysis of inositol phosphates and phospholipids, SHIP contributes to anti-proliferative biochemistry by blocking protein-protein interactions.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle.

The inositol 5-phosphatase SHIP (SHIP-1) is a negative regulator of signal transduction in hematopoietic cells and targeted disruption of SHIP in mice leads to a myeloproliferative disorder. We analyzed the effects of SHIP on the human leukemia cell line Jurkat in which expression of endogenous SHIP protein is not detectable. Restoration of SHIP expression in Jurkat cells with an inducible expression system caused a 69% reduction of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) and a 65% reduction of Akt kinase activity, which was associated with reduced phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) (Ser-9) without changing the phosphorylation of Bad (Ser-136), FKHR (Ser-256) or MAPK (Thr-202/Tyr-204). SHIP-expressing Jurkat cells showed an increased transit time through the G1 phase of the cell cycle, but SHIP did not cause a complete cell cycle arrest or apoptosis. Extension of the G1 phase was associated with an increased stability of the cell cycle inhibitor p27(Kip1) and reduced phosphorylation of the retinoblastoma protein Rb at serine residue 780. Our data indicate that restoration of SHIP activity in a human leukemia cell line, which has lost expression of endogenous SHIP, downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle.

Apoptosis↗
PubMed1999

The src homology domain 2-containing inositol phosphatase SHIP forms a ternary complex with Shc and Grb2 in antigen receptor-stimulated B lymphocytes.

The inositol phosphatase SHIP has been implicated in signaling events downstream of a variety of receptors and is thought to play an inhibitory role in stimulated B cells. We and others have reported that SHIP is rapidly tyrosine phosphorylated upon B cell antigen receptor (BCR) cross-linking and forms a complex with the adapter protein Shc. Here, we report that cross-linking of the BCR induces association between Grb2 and SHIP as well as association between Shc and SHIP. We made use of a Grb2-deficient B cell line to demonstrate both in vitro and in vivo that Grb2 expression is required for the efficient association between Shc and SHIP. The results indicate that SHIP, Shc, and Grb2 form a ternary complex in stimulated B cells, with Grb2 stabilizing the interaction between Shc and SHIP. The interactions between Shc, Grb2, and SHIP are therefore analogous to the interactions between Shc, Grb2, and SOS. Shc and Grb2 may help to localize SHIP to the cell membrane, regulating SHIP's inhibitory function following BCR stimulation.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Homeostasis and regeneration of the hematopoietic stem cell pool are altered in SHIP-deficient mice.

SH2-containing inositol 5-phosphatase (SHIP) is an important negative regulator of cytokine and immune receptor signaling. SHIP-deficient mice have a number of hematopoietic perturbations, including enhanced cytokine responsiveness. Because cytokines play an important role in the maintenance/expansion of the primitive hematopoietic cell pool, we investigated the possibility that SHIP also regulates the properties of cells in these compartments. Primitive hematopoietic cells were evaluated in SHIP-deficient mice and wild-type littermate controls using the colony-forming unit-spleen (CFU-S) and competitive repopulating unit (CRU) assays for multipotent progenitors and long-term lympho-myeloid repopulating cells, respectively. Absence of SHIP was found to affect homeostasis of CFU-S and CRU compartments. Numbers of primitive cells were increased in extramedullary sites such as the spleen of SHIP-deficient mice, although total body numbers were not significantly changed. In vivo cell cycle status of the CRU compartment was further evaluated using 5-fluorouracil (5-FU). SHIP-deficient CRUs were more sensitive to 5-FU killing, indicating a higher proliferative cell fraction. More strikingly, SHIP was found to regulate the ability of primitive cells to regenerate in vivo, as CRU recovery was approximately 30-fold lower in mice that received transplants of SHIP-deficient cells compared with controls. These results support a major role for SHIP in modulating pathways important in homeostasis and regeneration of hematopoietic stem cells, and emphasize the importance of negative cytokine regulation at the earliest stages of hematopoiesis.

Animals↗
PubMed1984

Shipping suppresses lymphocyte blastogenic responses in Angus and Brahman X Angus feeder calves.

An experiment using 40 Angus or Brahman X Angus preconditioned feeder calves was conducted to evaluate the influence of shipping on cellular immune reactivity. Steers were allotted on the basis of weight and breed to a control or shipped group. Shipped steers were trucked 700 km to a feedlot; control steers remained at the ranch of origin. Total and differential leukocyte counts, phytohemagglutinin skin-test responses, lymphocyte blastogenic responses, monocyte phagocytic function, packed cell volumes and concentrations of plasma cortisol were determined before, immediately after and 1 wk after shipment. At unloading, total leukocytes were increased (P less than .05) in shipped Angus steers. Shipped steers also had higher (P less than .01) numbers of neutrophils. Skin-test responses to phytohemagglutinin were higher (P less than .05) in Angus than in Brahman X Angus steers, but shipping did not influence the reaction. Lymphocyte blastogenic responses were lower (P less than .05) in shipped steers; however, cortisol levels in plasma were not elevated (P greater than .10) in shipped calves. Monocyte phagocytosis and packed cell volume were not influenced by shipping. These data suggest that shipped steers have suppressed lymphocyte blastogenic responses.

Animals↗
PubMed1999

Tyrosine phosphorylation of shc in response to B cell antigen receptor engagement depends on the SHIP inositol phosphatase.

Tyrosine phosphorylation of Shc in response to B cell Ag receptor (BCR) engagement creates binding sites for the Src homology 2 (SH2) domain of Grb2. This facilitates the recruitment of both Grb2. Sos complexes and Grb2. SHIP complexes to the plasma membrane where Sos can activate Ras and SH2 domain-containing inositol phosphatase (SHIP) can dephosphorylate phosphatidylinositol 3,4,5-trisphosphate. Given the importance of Shc phosphorylation, we investigated the mechanism by which the BCR stimulates this response. We found that both the SH2 domain and phosphotyrosine-binding (PTB) domain of Shc are important for BCR-induced tyrosine phosphorylation of Shc and the subsequent binding of Grb2 to Shc. The unexpected finding that the PTB domain of Shc is required for Shc phosphorylation was investigated further. Because the major ligand for the Shc PTB domain is SHIP, we asked whether the interaction of Shc with SHIP was required for BCR-induced tyrosine phosphorylation of Shc. Using SHIP-deficient DT40 cells, we show that SHIP is necessary for the BCR to induce significant levels of Shc tyrosine phosphorylation. BCR-induced tyrosine phosphorylation of Shc could be restored in the these cells by expressing wild-type SHIP but not by expressing a mutant form of SHIP that cannot bind to Shc. This suggests that BCR-induced tyrosine phosphorylation of Shc may depend on the binding of SHIP to the Shc PTB domain. Thus, we have described a novel role for SHIP in BCR signaling, promoting the tyrosine phosphorylation of Shc.

Adaptor Proteins, Signal Transducing↗