|Coordinate||52,640,733 bp (GRCm38)|
|Base Change||A ⇒ G (forward strand)|
|Gene Name||spleen tyrosine kinase|
|Chromosomal Location||52,583,173-52,648,792 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the family of non-receptor type Tyr protein kinases. This protein is widely expressed in hematopoietic cells and is involved in coupling activated immunoreceptors to downstream signaling events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. It is thought to be a modulator of epithelial cell growth and a potential tumour suppressor in human breast carcinomas. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]
PHENOTYPE: Homozygous null mice have high rates of postnatal lethality, exhibit developmental defects of B cells, T cells and osteoclasts, and have defective dendritic cell cross-presentation of antigens from necrotic cells. [provided by MGI curators]
|Amino Acid Change||Tyrosine changed to Cysteine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000060828] [ENSMUSP00000112914] [ENSMUSP00000113852]|
AA Change: Y501C
|Predicted Effect||possibly damaging
PolyPhen 2 Score 0.798 (Sensitivity: 0.84; Specificity: 0.93)
AA Change: Y478C
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
AA Change: Y501C
|Predicted Effect||possibly damaging
PolyPhen 2 Score 0.798 (Sensitivity: 0.84; Specificity: 0.93)
|Meta Mutation Damage Score||0.31|
|Is this an essential gene?||Essential (E-score: 1.000)|
|Candidate Explorer Status||CE: failed initial filter|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Live Mice|
|Last Updated||2017-09-14 11:55 AM by Anne Murray|
|Record Created||2013-02-01 12:40 AM by Ying Wang|
The poppy phenotype was initially identified by flow cytometric analysis of peripheral blood from G3 mice carrying mutations induced by N-ethyl-N-nitrosourea (ENU). The index poppy mice (T2313, T2314, and T2315) were deficient in B cells; neutrophil numbers were increased (Figure 1 & 2). Peritoneal macrophages from poppy mice exhibited hypersensitivity to the Toll-like receptor (TLR) agonists LPS, MALP2 and R848 as determined by increased secretion of TNFα compared to wild type macrophages (Figure 3).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 56 mutations. Seventeen G3 mice from the poppy pedigree were genotyped at all 56 mutation sites. Among six mice with the poppy phenotype, five were homozygous and one was heterozygous for a mutation in Syk on chromosome 13. Among eleven unaffected mice, eight were either heterozygous or wild type at the Syk locus, while three were homozygous for the Syk mutation, indicating that the poppy phenotype is recessive and incompletely penetrant. These data resulted in a LOD score of 5.30. The mutation is an A to G transition at base pair 52640733 (v38) on Chromosome 13 in the GenBank genomic region NC_000079 encoding Syk. The mutation corresponds to residue 1718 in the NM_011518 mRNA sequence and 1714 in the NM_001198977 mRNA sequence within exon 11 of 14 total exons.
The mutated nucleotide is indicated in red. The mutation results in a tyrosine (Y) to cysteine (C) substitution at residue 501.
Syk encodes spleen tyrosine kinase (Syk), one of two members of the Syk family of cytosolic protein kinases. The second Syk family member is zeta-chain-associated protein kinase 70 (Zap70) (see the records for murdock, trebia, wanna, and mrtless). Syk and Zap70 both have two Src homology 2 (SH2) domains and a C-terminal kinase region followed by a short C-terminal tail [Figure 4; reviewed in (1-3)]. Between the SH2 domains is interdomain A; between the C-terminal SH2 domain and the kinase domain is interdomain B [(4); reviewed in (1-3)].
The SH2 domains recognize and bind diphosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs; (Asp/Glu)-X-X-Tyr-X-X-Leu/Iso-(X)6-12-Tyr-X-X-Leu/Iso) or hemi-ITAMs (i.e,. contain one Tyr) in a target protein as well as β3-integrin (ITAM-independent) to initiate downstream signaling [reviewed in (1-3;5;6)]. The SH2 domains of Syk have a conformational flexibility that can recognize the relative distance between phosphotyrosines of an ITAM and adjust the orientation of the SH2 domains to fit that spacing [(7); reviewed in (5)]. The flexibility of the SH2 domains allows for Syk to interact with several different immunoreceptors (e.g., B- and T-cell antigen receptors and Natural Killer (NK)-cell receptors) and, possibly, some G-protein-coupled receptors [reviewed in (5)].
Interdomain A facilitates the proper conformation of the SH2 domains to promote binding to phosphorylated ITAMs using a helical coiled-coil structure [reviewed in (1;2)]. In addition, the C-terminal portion of interdomain A is critical for calcium mobilization via B cell receptor (BCR) signaling (8).
Interdomain B contains five putative autophosphorylation sites and functions to recruit, and dock, downstream signaling proteins (e.g., phospholipase Cγ1 (PLCγ1), Vav1 and c-Cbl) as well as regulate the ability of Syk to bind to ITAMs [(9-13); reviewed in (1;2;14)]. Interdomain B also contains a non-canonical nuclear localization signal that permits Syk to shuttle between the nucleus and cytoplasm (15;16). A splice variant of Syk, SykB, lacks 23 amino acids of interdomain B, a sequence necessary for maximal ITAM binding by Syk [(12;15;17)]. SykB has comparable enzymatic activity to that of Syk, but is less efficient in coupling to phosphorylated ITAMs such as those of the FcγRI receptor of mast cells [(12); reviewed in (1;14)].
The Syk kinases are maintained in a closed, inactive conformation by interactions between residues in interdomain A, interdomain B, and the kinase domain (36;38;39). The C-terminal region of interdomain A contains residues important for maintaining the resting state [(8); reviewed in (2)]. In the inactive conformation, the SH2 domains are not aligned for ITAM binding and the kinase domain cannot perform the phospho-transfer reaction (36). Either phosphorylation of interdomain A/B tyrosines or binding of phosphorylated ITAMs to SH2 domains can release the inhibitory interactions that hold Syk in an inactive state, thereby permitting ATP and substrates access to the active site and stimulating Syk kinase activity (36;37;39).
The crystal structure of the kinase domain of human Syk (amino acids 353-635) has been solved [Figure 5; PDB: 1XBA; (40)]. The N-terminal lobe of the kinase domain is composed of a five-stranded β-sheet and a single α-helix, while the C-terminal lobe is largely α-helical with three short β-strands; the active site is between the two lobes (40). Unphosphorylated Syk kinase domain forms a loop-out conformation similar to what is seen in active, phosphorylated protein kinases, indicating that activation loop phosphorylation is not required for Syk kinase activity. A recent study crystalized full-length human Syk at 2.2 Å [Figure 6; PDB:4FL3; (41)]. In this structure, the topology of the Syk kinase domain is similar to inactive kinase domains. The interdomain linkers (helices αL1, αL2, and αL3) bind to helices αE and αI of the kinase domain, consistent with previous data supporting an autoinhibited conformation maintained by interactions between interdomains A and B, and the kinase domain. The SH2 domains each consist of a β-sheet flanked by two α-helices and the linkers consist of three α-helices to form a helical coiled coil (41).
The poppy mutation is a tyrosine to cysteine substitution at amino acid 501 within the C-terminal kinase domain.
Syk is highly expressed in hematopoietic cells including B cells, immature T cells, mast cells, dendritic cells, basophils, osteoclasts, leukocytes, neutrophils, macrophages, and platelets [reviewed in (1-3)]. Syk is also expressed in non-hematopoietic cells including fibroblasts (embryonic and nasal), epithelial cells (breast and airway), hepatocytes, neuronal cells, and vascular endothelial cells, red blood cells, and synoviocytes (4).
In B cells, Syk is localized to both nuclear and cytoplasmic compartments [reviewed in (1)]. The mechanism by which Syk is transported between the nucleus and cytoplasm is unknown, but interdomain B is essential for this to occur (16). Upon BCR aggregation, Syk is recruited to the plasma membrane [(42); reviewed in (1)].
Reduction in Syk mRNA and protein expression has been documented in several types of cancers including breast, gastric, melanoma, squamous cell carcinoma, pro-B cell acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) [(43-47); reviewed in (48)].
Syk plays a major role in B cell development as a component of the pre-BCR and BCR signaling pathways, and no mature B cells are found in mice with targeted null mutations of Syk (49-51). In BCR signaling, following the aggregation of BCR molecules, the ITAMs in the tails of Igα and Igβ become phosphorylated by Src family kinases (typically Lyn) [Figure 7; (52;53)]. These phosphotyrosines then act as docking sites for the SH2 domains of Syk, resulting in Syk phosphorylation and activation. Syk phosphorylates a number of downstream targets including BLNK (see the record for busy), PLCγ2 (see the record for queen), and protein kinase C β (PKCβ; see the record for Untied). BCR stimulation also activates phosphatidylinositol 3 kinase (PI3K) resulting in the generation of PIP3, which binds selectively to the pleckstrin homology domain of Btk, facilitating membrane recruitment of the kinase. Phosphorylated BLNK also provides docking sites for Btk, as well as PLCγ2, which results in the additional phosphorylation and activation of PLCγ2 by Btk leading to the hydrolysis of phosphatidylinositol-3,4-diphosphate (PIP2) to inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (54). The recruitment of Vav1, Nck and Ras by BLNK to the BCR activates MAP kinase cascades such as JNK, p38 and extracellular signal regulated kinase (ERK) [reviewed in (55)]. Together, these signals allow the activation of multiple transcription factors, including nuclear factor of activated T cells (NF-AT), NF-κB (see the records for puff, xander and panr2) and AP-1, which subsequently regulate biological responses including cell proliferation, differentiation, and apoptosis as well as the secretion of antigen-specific antibodies [reviewed in (56)]. Other molecules that play important roles in BCR signaling include Bcl10, mucosa-associated lymphoid tissue translocation gene 1 (Malt1), and caspase recruitment domain family, member 11 (CARMA1, alternatively Card11; see the record for king), which are involved in NF-κB activation along with PKCβ (57-60).
Syk couples pre-BCR and BCR activation to downstream signaling pathways that mediate B cell development, proliferation, and survival (Figure 7). Pre-BCR engagement results in the activation of Syk, which together with Src-family kinases (Lyn, Fyn, Blk), phosphorylates many substrates (see Table 1) and triggers signaling pathways that are involved in both proliferation and differentiation of pre-B cells (52;53). These include activation of phosphoinositide 3 kinase (PI3K) by phosphorylating the coreceptor CD19 and/or the adaptor protein B-cell PI3K adaptor (BCAP; see the record for sothe) (61). PI3K activation results in the generation of phosphatidylinositol-3,4,5-triphosphate (PIP3), which recruits plekstrin-homology domain signaling molecules to the membrane including the serine threonine protein kinase B (PKB) and its activating kinase 3-phosphoinositide-dependent protein kinase 1 (PDK1). Signaling through this pathway suppresses recombination-activating gene 1 (RAG1; see the record for maladaptive) and RAG2 expression (in VDJ recombination in pro-B cells), blocks Igκ (the kappa chain of the immunoglobin light chain) gene recombination, and induces cell proliferation. Syk also phosphorylates SH2-domain containing leukocyte protein of SLP65, resulting in the organization of a molecular complex that includes Bruton’s tyrosine kinase (BTK) and PLCγ2 (54). This complex controls downregulation of l-5, a component of the surrogate light chain (SLC), and upregulates the expression of RAG proteins and the interferon-regulatory factor 4 (IRF4). IRF4 positively regulates Igκ recombination. SLP65 also modulates PKB activity either directly or by altering the activity of Syk, CD19, or PI3K. Alternatively, SLP65 may regulate PKB activity by activating lipid phosphatases such as SH2-domain containing inositol-5 phosphate (SHIP; see the record for styx) and altering PIP3 levels.
Table 1. Select substrates of Syk* [modified from (1)]
*List is not comprehensive
Syk in other immune cell ITAM pathways
In addition to its role in BCR signaling, Syk also functions in pre-TCR signaling in thymocytes during the transition from the DN3 to the DN4 stage of development (89), and during TCR signaling in mature T cell populations (intraepithelial γδ T cells and naïve αβ T cells) (Table 2) (90;91). However, Zap70 is the major Syk family kinase in TCR signaling.
Syk functions in ITAM-associated signaling in other immune cells including natural killer cells downstream from the FcγRIII receptor (92), in mast cells downstream from the FcεRI receptor (11;13), and in neutrophils and macrophages downstream from FcγR signaling [Figure 8 and Table 2; (93;94)]. Although ligand recognition differs among these receptors, the intracellular pathways are highly conserved: activated Src family kinases (e.g., Hck, Fgr, Lyn, or Src) recruit Syk to the receptor-associated ITAMs [reviewed in (3;95)]. Activated Syk subsequently phosphorylates a number of proteins including SLP76, SLP65, Vav1, PLCγ, and the p85α subunit of PI3K (see Table 1). These proteins activate downstream signaling components to trigger several cellular responses including proliferation, differentiation, cell survival, mast cell degranulation, reactive oxygen species (ROS) production, phagocytosis, and cytokine release [reviewed in (2;3)].
A role for Syk in numerous non-immune cells has also been demonstrated (Table 2).
Syk signaling via hemi-ITAMs
Syk can also bind to hemi-ITAMs (i.e., ITAM motifs containing one YxxL motif) in C-type lectin receptors including the C-type lectin-like protein type 2 (CLEC2) receptor, CLEC9A, and Dectin-1 (96). CLEC2 functions in the developmental separation of blood and lymphatic vessels (97;98), while Dectin-1 induces intracellular signaling upon recognition of fungal pathogens (99). The C-type lectin and BCR signaling pathways share many of the same downstream components, including PLCγ2 (96).
Syk-associated signaling via ITAM-signaling adaptors
Syk can also signal through ITAM-containing adaptors (e.g., DNAX activation protein-12 (DAP12) and FcRγ) that associate with immunoglobulin superfamily-containing proteins [e.g., Fc receptors, PIR-A, OSCAR, GPVI, or triggering receptor expressed on myeloid cells (TREM) (100;101)], C-type lectin receptors [e.g., Dectin-2, Mincle, or MDL-1 (102;103)], and cytokine receptors [e.g., macrophage colony-stimulating factor (M-CSF) (104;105)], as well as integrins (106;107). DAP12, FcRγ, and their associated receptors are found in several cell types including neutrophils, macrophages, monocytes, dendritic cells, basophils, eosinophils, mast cells, NK cells, microglia, osteoclasts, megakaryocytes, and platelets [reviewed in (108)]. Signaling via the ITAM-containing adaptors and their associated receptors is similar to ITAM receptor signaling. Syk-mediated activation of PLCγ2 and CARD9 leads to the activation of NF-κB and MAPKs [reviewed in (109)]. Signaling via the ITAM-signaling adaptors mediates phagocytosis (110) and osteoclast development (111) as well as cell proliferation and survival (105).
The ITAM-associated receptors and TLRs activate distinct signaling pathways, but the two pathways can cross-talk to activate NF-κB and the MAPKs. For example, Syk activation and association with DAP12-TREM can either amplify or dampen TLR-induced signals in a ligand-dependent manner during an inflammatory response, possibly through the CARD complex or the activation of ERK (112).
Integrins are known to signal via Syk in a pathway similar to that used by ITAM-associated immunoreceptors. For example, in platelets, activation of αIIbβ3 integrin (in association with the ITAM-containing receptor FcγRIIA) can activate Syk, subsequently leading to platelet activation through SLP76 and PLCγ2 [reviewed in (3)]. However, some evidence suggests that integrins activate Syk in an ITAM-independent manner, through direct binding between Syk and the integrin β chain [reviewed in (3)].
Table 2. Syk is a multi-functional kinase [modified from (5)]
Syk signaling affects several tumor cell activities including cell division, cell survival, 3-D cell outgrowth, cell migration, neuron-like cell differentiation, phagocytosis, and cell adhesion (47;48;133;134). Syk is expressed in human breast tissue and benign breast tumors, but is undetectable or expressed at low levels in invasive breast tumors and cell lines (47). Syk transfection into a Syk-negative breast cancer cell line resulted in inhibition of tumor growth and metastasis in athymic mice (47). In addition, overexpression of a kinase-deficient Syk in a Syk-expressing breast cancer cell line increased the incidence and growth of tumors (47). Thus, Cooper et al. propose that Syk functions as a tumor suppressor in human breast carcinomas (47). Consistent with this hypothesis, reduced amounts of SYK mRNA expression in breast cancer tissue relative to adjacent non-cancerous tissue were correlated with increased incidence of distant metastasis, translating to poor prognosis (135). Syk has been shown to regulate mammalian target of rapamycin (mTOR) and MAPK signaling in AML (44) and in B cell lymphoma (48;49). Syk is activated in CLL (45;46), a condition characterized by the expansion of monoclonal, mature B cells [reviewed in (136)], and regulates the survival of CLL B cells (137). Syk inhibition can suppress CLL B cell activation and migration (43).
Syk null mouse models
Syk deficiency in homozygous Syk knockout mouse models (MGI:1857421, MGI:2384078, and MGI: 3690645) leads to the absence of mature B cells due to abnormal B cell differentiation (49-51). Homozygotes exhibited early postnatal lethality (49;51) with a concomitant defect in blood vessel morphology, dilated vasculature, and systemic hemorrhage in the embryo (49;51;98;141). Further observation of homozygous Syktm1Tyb mice (MGI:2384078) found that the model exhibited defective osteoclast differentiation (111), decreased bone resorption (111), decreased TNF secretion from neutrophils after 16-hour culture with S. aureus or E. coli (142), impaired lymphatic vessel morphology in the lungs and brain [i.e., there is a connection between the vasculature and lymphatic systems; (98)], impaired neutrophil degranulation in response to S. aureus and E. coli (142), impaired neutrophil phagocytosis of bacteria (142), reduced T cell number in the skin (49), and inefficient CD8α+ dendritic cell antigen cross-presentation (143).
Consistent with an essential role for Syk in BCR signaling, B cell proliferation, and B cell differentiation (49;50;144), homozygous poppy mice are B cell-deficient. However, homozygous poppy mice are born at expected Mendelian ratios and survive to adulthood, indicating that the poppy allele retains sufficient functionality to support postnatal survival.
The role of Syk in TLR-mediated signaling is unclear. The poppy mutation results in an increase in macrophage TNFα secretion upon treatment with the TLR agonists MALP2 (TLR2/6) and R848 (TLR7). Studies have documented elevated TLR4-, TLR3-, and TLR9-mediated signaling in Syk-deficient macrophages, leading to a subsequent increase in TNF production relative to wild type macrophages (145). However, the role of Syk in TLR2/6, TLR7 or TLR8 signaling has not been documented.
Some evidence suggest that TLR or TNF receptor activation leads to integrin activation [(88;146); reviewed in (109)], subsequently causing the integrins to assume a conformation that promotes high-affinity ligand-binding in a process known as ‘inside-out’ signaling (147;148). Inside-out signaling promotes increased adhesion to the extracellular matrix, cell spreading and enhanced cell-cell interactions. The increased integrin ligand affinity also results in high-avidity ligation of integrins and the subsequent generation of an integrin-mediated ‘outside-in’ signal. The outside-in signal of β2 and β3 integrins is propagated by DAP12 and FcRγ, which recruit Syk to their phosphorylated ITAMs.
Published data currently support two distinct mechanisms by which Syk may negatively regulate TLR signaling. First, Syk interacts with, and induces the phosphorylation of, the TLR adapters MyD88 and TRIF (88). Phosphorylation of MyD88 and TRIF subsequently results in c-Cbl-induced ubiquitination and degradation of Syk (88). Second, β2 integrins and FcγRs in macrophages signal via the ITAM-containing adaptor DAP12 and Syk to inhibit TLR signaling through the induction of IL-10 and the TLR signaling inhibitors SOCS3, ABIN-3, and A20 (149). Notably, DAP12-deficient macrophages also displayed elevated TNF production in response to TLR ligands (145), supporting a DAP12 negative regulatory signaling cascade involving Syk that inhibits TLR signaling.
These findings contrast with data supporting a positive role for Syk in TLR signaling. In one study, Syk phosphorylation was induced in THP1 human monocytes upon TLR9 activation, subsequently leading to cell migration, adhesion, and secretion of IFNα and IL-6 (150). In another study, LPS stimulation of murine macrophages induced Syk phosphorylation and the expression of inflammatory genes (151). Piceatannol, a Syk inhibitor, as well as Syk inhibition by antisense oligonucleotides resulted in attenuation of the LPS-induced events in macrophages (151;152). Lin et al. examined the role of Syk in TLR9, -3, and -4-mediated signaling by using Syk inhibitors (SykI and BAY61-3606) in TLR-stimulated RAW 264.7 macrophages and primary bone marrow-derived macrophages (BMDM) (153). They found that pharmacological inhibition of Syk in the RAW 264.7 macrophages resulted in an inhibitory effect on TLR-induced JNK activation and the attenuation of inflammatory gene expression (iNOS and COX2); IKK, p38 and ERK activation were not changed (153). However, siRNA-mediated knockdown of Syk in RAW 264.7 cells followed by treatment with LPS, CpG, or poly(I:C) did not result in changes to JNK activation although there was an observed increase in iNOS and COX-2 expression (153). Chaudhary et al. treated human monocyte THP-1 cells with piceatannol and found that Syk activity is necessary for TLR4 tyrosine phosphorylation upon LPS stimulation and that piceatannol treatment results in an inhibition of IL-10 and IL-12 release from the THP-1 cells upon LPS stimulation (154).
Poppy genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition. The same primers are used for PCR amplification and for sequencing.
Poppy(F): 5’- CCGCCGTCCACTCTTGGTAATG-3’
Poppy(R): 5’- TGTTTCAAAGCAAGTTGACGCAAGC-3’
Poppy_seq(F): 5’- CAGGTTTCCATGGGGATGAA-3’
1) 94°C 2:00
2) 94°C 0:30
3) 55°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 40X
6) 72°C 10:00
7) 4°C ∞
The following sequence of 797 nucleotides (from Genbank genomic region NC_000079 for the linear DNA sequence of Syk) is amplified:
57130 c cgccgtccac tcttggtaat gatgtcgtgt gattctaggc acattaagga
57181 taagaacatc atagagctgg ttcaccaggt ttccatgggg atgaagtatt tggaagagag
57241 caactttgtg cacagagatc tggctgcgcg gaacgtgctt ctggtcacac agcactatgc
57301 caagatcagc gatttcggtc tttccaaagc cctgcgtgct gatgaaaact actacaaggt
57361 aggagcgctc ggtgcaagct cacagaacag ggagaggaaa cagctctgtg caggctcacg
57421 gagcaggctg agagctcagt acaggctcac agagcagctg aggggacagc ttccatgcat
57481 agttaaggtt gcaggttata aagatataga aagataaatg tgtgctctct gtattttact
57541 atggtagaaa tctcactagt aaccttggag aaaagtattc ttaagatcga ttctgtccat
57601 caagaaacac aaaccaaaaa tactgtaatg tttctcaact ggaatctttt tcagactagg
57661 atcttatgtt gagttttttg gtggtggtgg tggttttttt tttttttttt ttcgttttac
57721 atttacttat cttgctctgt gtatggagtc atgtgtgccg tagtgttcta atagagagca
57781 gaggacaact tacagaagtt gattctctcc atctaccatg catatcggag gaatcgaact
57841 ctgatcttcg gattcggcag caggcacctt acccattgag ccatcttgct ggcctctaaa
57901 tgcttgcgtc aacttgcttt gaaaca
Primer binding sites are underlined and the sequencing primer is highlighted; the mutated A is shown in red text.
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|Science Writers||Eva Marie Y. Moresco, Anne Murray|
|Authors||Ying Wang, Hexin Shi, Ming Zeng, Bruce Beutler|