Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice

Fukao, Takanori; Yamada, Taketo; Tanabe, M.; Terauchi, Yasuo; Ota, Takayuki; Takayama, Tetsuro; Asano, Tomohiko; Takeuchi, Tsutomu; Kadowaki, Takashi; Hata, Jun Ichi; Koyasu, Shigeo

doi:10.1038/ni768

Cited by 181 publications

(158 citation statements)

References 56 publications

Supporting

Mentioning

146

Contrasting

Order By: Relevance

“…However, it is also clear that PI 3-kinase has additional roles in proliferation induced by SCF and GM-CSF not related to Erk1/2 activation, because LY294002 completely blocked proliferation by these factors. This is in agreement with other studies showing that PI 3-kinase is essential for c-Kit-dependent growth and tumorigenesis (32)(33)(34)(35). DISCUSSION SCF dramatically enhances growth when combined with other cytokines (11).…”

Section: Fig 4 Scf-and Gm-csf-induced Phosphorylation Of C-kitsupporting

confidence: 92%

“…This points to a central role for PI 3-kinase in proliferation induced by SCF and GM-CSF alone or in combination, besides its effect on MAP kinase phosphorylation kinetics. This is supported by studies using mast cells from p85␣-deficient mice, which display defects in many c-Kit-mediated functions, including reduced SCF-induced proliferation (34,35).…”

Section: Scf-and Gm-csf-mediated Synergy 44551mentioning

confidence: 88%

See 1 more Smart Citation

Synergistic Growth of Stem Cell Factor and Granulocyte Macrophage Colony-stimulating Factor Involves Kinase-dependent and -independent Contributions from c-Kit

Lennartsson

Shivakrupa

Linnekin

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Stem cell factor (SCF) binds and activates the receptor tyrosine kinase c-Kit, and this interaction is critical for normal hematopoiesis. SCF also synergizes with a variety of growth factors, including those binding members of the cytokine receptor superfamily. The mechanisms mediating this synergy remain to be defined. The present study investigates both structural and biochemical cross-talk between c-Kit and the receptor for granulocyte macrophage colony-stimulating factor (GM-CSF). We have found that c-Kit forms a complex with the ␤-chain of the GM-CSF receptor, and this interaction involves the first part of the c-Kit kinase domain. Although inhibition of c-Kit kinase activity completely blocked SCF-induced proliferation, there was still greater than additive growth induced by SCF in combination with GM-CSF. In contrast, an inhibitory antibody against the extracellular domain of c-Kit (K-27) completely inhibited growth in response to SCF alone or in combination with GM-CSF. These results support a kinase-independent component of the synergistic growth induced by SCF and GM-CSF that may relate to interaction of these receptors. It is also clear that a significant part of the synergistic growth is dependent of c-Kit kinase activity. Although synergistic increases in phosphorylation of c-Kit and the ␤-chain of the GM-CSF receptor were not observed, SCF and GM-CSF in combination prolonged the duration of Erk1/2 phosphorylation in a phosphatidylinositol 3-kinase-dependent manner. Consistent with these findings, phosphatidylinositol 3-kinase is synergistically activated by SCF and GM-CSF together. Hence, c-Kit makes both kinase-independent and -dependent contributions to the proliferative synergy induced by SCF in combination with GM-CSF.The mechanisms mediating hematopoiesis are not fully understood but require interactions between a wide array of cell surface receptors with growth factors and cytokines. Two receptor families important for hematopoiesis are the cytokine receptor superfamily and the receptor tyrosine kinase superfamily. Ligands for the cytokine receptors include granulocyte macrophage colony-stimulating factor (GM-CSF), 1 interleukin-3 (IL-3), and erythropoietin (Epo). The receptor for human GM-CSF is comprised of a GM-CSF-specific ␣-chain and a ␤-chain shared with the receptors for IL-3 and IL-5 (1, 2). Upon GM-CSF stimulation the ␣-and ␤-chains cluster together, bringing associated cytoplasmic tyrosine kinases close together resulting in activation and subsequent tyrosine phosphorylation of the ␤-chain. Stem cell factor (SCF) binds to the receptor tyrosine kinase c-Kit leading to its homodimerization and autophosphorylation (3). Phosphorylated tyrosine residues, in cKit and the ␤-chain, function as docking sites for signal transduction molecules with SH2 domains. The SH2 domain is a stretch of ϳ100 amino acids that binds phosphorylated tyrosine residues in an amino acid sequence context-dependent manner (4).Previous studies have suggested that c-Kit may play a role in responses mediated by IL-3 ...

show abstract

Section: Fig 4 Scf-and Gm-csf-induced Phosphorylation Of C-kitsupporting

confidence: 92%

Section: Scf-and Gm-csf-mediated Synergy 44551mentioning

confidence: 88%

Synergistic Growth of Stem Cell Factor and Granulocyte Macrophage Colony-stimulating Factor Involves Kinase-dependent and -independent Contributions from c-Kit

Lennartsson

Shivakrupa

Linnekin

2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…SHIP1 negatively regulates PI3K activation via its phosphatase activity and can also act as a signaling adaptor (33). Other investigators have reported that the loss of the p85␣ subunit of class IA PI3K causes selective loss of gastrointestinal mast cells but does not affect mast cell degranulation in vitro or PSA in vivo (34). Loss of the p110␦ subunit of PI3K (class IA) results in reductions in numbers of some dermal mast cells, degranulation, cutaneous anaphylaxis, and TNF and IL-6 production (35).…”

Section: Discussionmentioning

confidence: 99%

SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo

Haddon

Antignano

Hughes

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

SHIP1 inhibits immune receptor signaling through hydrolysis of the PI3K product phosphatidylinositol 3,4,5-trisphosphate, forming phosphatidylinositol 3,4-bisphosphate. In mast cells, SHIP1 represses FcεRI- and cytokine-mediated activation in vitro, but little is known regarding the function of SHIP1 in mast cells in vivo or the susceptibility of Ship1−/− mice to mast cell-associated diseases. In this study, we found that Ship1−/− mice have systemic mast cell hyperplasia, increased serum levels of IL-6, TNF, and IL-5, and heightened anaphylactic response. Further, by reconstituting mast cell-deficient mice with Ship1+/+ or Ship1−/− mast cells, we found that the above defects were due to loss of SHIP1 in mast cells. Additionally, we found that mice reconstituted with Ship1−/− mast cells suffered worse allergic asthma pathology than those reconstituted with Ship1+/+ mast cells. In summary, our data show that SHIP1 represses allergic inflammation and mast cell hyperplasia in vivo and exerts these effects specifically in mast cells.

show abstract

“…The PI3Ks and their downstream target serine/threonine kinase Akt (also known as protein kinase B) are a conserved family of signal transduction enzymes that are involved in regulating cellular activation, inflammatory responses, chemotaxis, and apoptosis (20). We (5,21,22) and others (23)(24)(25) have reported that the PI3K/Akt signaling pathway may be an endogenous negative feedback regulator or compensatory mechanism that serves to limit proinflammatory and apoptotic events in response to injurious stimuli. Indeed, activation of PI3K/Akt-dependent signaling has been shown to prevent cardiac myocyte apoptosis and protect the myocardium from I/R injury (26 -29).…”

Section: Protection Against Myocardial Ischemia/reperfusion Injury Inmentioning

confidence: 99%

Protection against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated through a Phosphoinositide 3-Kinase-Dependent Mechanism

Fang¹,

Ha²,

Ma³

et al. 2007

The Journal of Immunology

147

161

View full text Add to dashboard Cite

TLRs play a critical role in the induction of innate and adaptive immunity. However, TLRs have also been reported to mediate the pathophysiology of organ damage following ischemia/reperfusion (I/R) injury. We have reported that TLR4−/− mice show decreased myocardial injury following I/R; however, the protective mechanisms have not been elucidated. We examined the role of the PI3K/Akt signaling pathway in TLR4−/− cardioprotection following I/R injury. TLR4−/− and age-matched wild-type (WT) mice were subjected to myocardial ischemia for 45 min, followed by reperfusion for 4 h. Pharmacologic inhibitors of PI3K (wortmannin or LY294002) were administered 1 h before myocardial I/R. Myocardial infarct size/area at risk was reduced by 51.2% in TLR4−/− vs WT mice. Cardiac myocyte apoptosis was also increased in WT vs TLR4−/− mice following I/R. Pharmacologic blockade of PI3K abrogated myocardial protection in TLR4−/− mice following I/R. Specifically, heart infarct size/area at risk was increased by 98% in wortmannin and 101% in LY294002-treated TLR4−/− mice, when compared with control TLR4−/− mice. These data indicate that protection against myocardial I/R injury in TLR4−/− mice is mediated through a PI3K/Akt-dependent mechanism. The mechanisms by which PI3K/Akt are increased in the TLR4−/− myocardium may involve increased phosphorylation/inactivation of myocardial phosphatase and tensin homolog deleted on chromosome 10 as well as increased phosphorylation/inactivation of myocardial glycogen synthase kinase-3β. These data implicate innate immune signaling pathways in the pathology of acute myocardial I/R injury. These data also suggest that modulation of TLR4/PI3K/Akt-dependent signaling pathways may be a viable strategy for reducing myocardial I/R injury.

show abstract

Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice

Cited by 181 publications

References 56 publications

Synergistic Growth of Stem Cell Factor and Granulocyte Macrophage Colony-stimulating Factor Involves Kinase-dependent and -independent Contributions from c-Kit

Synergistic Growth of Stem Cell Factor and Granulocyte Macrophage Colony-stimulating Factor Involves Kinase-dependent and -independent Contributions from c-Kit

SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo

Protection against Myocardial Ischemia/Reperfusion Injury in TLR4-Deficient Mice Is Mediated through a Phosphoinositide 3-Kinase-Dependent Mechanism

Contact Info

Product

Resources

About