SLP adaptor and CSK-interacting membrane protein (SCIMP) is a small palmitoylated, single-pass transmembrane adaptor protein (TRAP family) expressed in antigen-presenting cells (B cells, dendritic cells, macrophages). It resides in tetraspanin-enriched microdomains of the plasma membrane, accumulates at the antigen-presenting-cell side of the immunological synapse and in macrophage ruffles and filopodia. Its proline-rich region constitutively binds the SH3 domain of LYN, and LYN/SYK-phosphorylated tyrosines recruit SH2-containing effectors (GRB2, SLP65/BLNK-SLP76, CSK, SYK). SCIMP acts as a non-TIR adaptor for Toll-like receptors: it binds the TLR4 TIR domain after LPS stimulation, scaffolds LYN, SYK and ERK1/2 to the receptor, is required for TLR4 tyrosine phosphorylation and selectively drives IL-6 and IL-12p40 production in macrophages. It also contributes to MHC-II reverse signalling (ERK activation) in B cell lines and to sustained Dectin-1 signalling in dendritic cells.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001726 ruffle | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: SCIMP concentrates in actin-rich dorsal ruffles of macrophages, the membrane domains where TLR4 is enriched and LPS signalling is initiated; Erk2 and Syk are recruited to SCIMP there (PMID:28098138, PMID:34496234, PMID:35337798). Reason: Well supported in mouse macrophages by immunofluorescence and immunogold EM, and consistent with SCIMP's role in TLR4 signalling from ruffles. Ruffles are one of several plasma membrane sub-domains SCIMP occupies; the core location is the plasma membrane (lipid-raft/tetraspanin domains), so this is retained as non-core. Human annotation is transferred from the mouse ortholog Q3UU41. Supporting Evidence: PMID:28098138 SCIMP staining was apparent on intracellular punctate membranes, but was particularly prominent on the macrophage plasma membrane, where it was further concentrated in cell surface projections, notably the filopodia and ruffles of some cells. PMID:34496234 SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling |
| GO:0001726 ruffle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCIMP concentrates in actin-rich dorsal ruffles of macrophages, the membrane domains where TLR4 is enriched and LPS signalling is initiated; Erk2 and Syk are recruited to SCIMP there (PMID:28098138, PMID:34496234, PMID:35337798). Reason: Well supported in mouse macrophages by immunofluorescence and immunogold EM, and consistent with SCIMP's role in TLR4 signalling from ruffles. Ruffles are one of several plasma membrane sub-domains SCIMP occupies; the core location is the plasma membrane (lipid-raft/tetraspanin domains), so this is retained as non-core. Human annotation is transferred from the mouse ortholog Q3UU41. Supporting Evidence: PMID:28098138 SCIMP staining was apparent on intracellular punctate membranes, but was particularly prominent on the macrophage plasma membrane, where it was further concentrated in cell surface projections, notably the filopodia and ruffles of some cells. PMID:34496234 SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling |
| GO:0001772 immunological synapse | IBA GO_REF:0000033 | ACCEPT | Summary: SCIMP was discovered as a palmitoylated transmembrane adaptor that localizes to the antigen-presenting-cell side of the immunological synapse via tetraspanin-enriched microdomains (PMID:21930792). Reason: Direct observation in human APC/B cell lines (PMID:21930792) and restated in the mouse Dectin-1 study. The IBA places this at the SCIMP clade (PTN000948237) seeded by the human IDA; consistent with the experimental record. Supporting Evidence: PMID:21930792 SCIMP is expressed in B cells and other professional APCs and is localized in the immunological synapse due to its association with tetraspanin-enriched microdomains. file:human/SCIMP/SCIMP-uniprot.txt Rapidly translocates into immunological synapse (IS) at cell-cell contacts between antigen-presenting cells (APCs) and T-cells (PubMed:21930792). |
| GO:0001772 immunological synapse | IDA PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | ACCEPT | Summary: SCIMP was discovered as a palmitoylated transmembrane adaptor that localizes to the antigen-presenting-cell side of the immunological synapse via tetraspanin-enriched microdomains (PMID:21930792). Reason: Direct observation in human APC/B cell lines (PMID:21930792) and restated in the mouse Dectin-1 study. The IBA places this at the SCIMP clade (PTN000948237) seeded by the human IDA; consistent with the experimental record. Supporting Evidence: PMID:21930792 SCIMP is expressed in B cells and other professional APCs and is localized in the immunological synapse due to its association with tetraspanin-enriched microdomains. file:human/SCIMP/SCIMP-uniprot.txt Rapidly translocates into immunological synapse (IS) at cell-cell contacts between antigen-presenting cells (APCs) and T-cells (PubMed:21930792). |
| GO:0001772 immunological synapse | IEA GO_REF:0000002 | ACCEPT | Summary: SCIMP was discovered as a palmitoylated transmembrane adaptor that localizes to the antigen-presenting-cell side of the immunological synapse via tetraspanin-enriched microdomains (PMID:21930792). Reason: Direct observation in human APC/B cell lines (PMID:21930792) and restated in the mouse Dectin-1 study. The IBA places this at the SCIMP clade (PTN000948237) seeded by the human IDA; consistent with the experimental record. Supporting Evidence: PMID:21930792 SCIMP is expressed in B cells and other professional APCs and is localized in the immunological synapse due to its association with tetraspanin-enriched microdomains. file:human/SCIMP/SCIMP-uniprot.txt Rapidly translocates into immunological synapse (IS) at cell-cell contacts between antigen-presenting cells (APCs) and T-cells (PubMed:21930792). |
| GO:0002720 positive regulation of cytokine production involved in immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Scimp-deficient bone-marrow-derived dendritic cells show reduced late-phase (beyond 24 h) cytokine production after Dectin-1 stimulation with zymosan (PMID:27288407). Reason: The knockout phenotype is real but restricted to sustained late-phase responses downstream of Dectin-1; early responses were normal. The best-established cytokine function of SCIMP is the TLR-driven IL-6/IL-12p40 output in macrophages, captured by the specific IL-6 and IL-12 production terms. Supporting Evidence: PMID:27288407 Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 |
| GO:0002720 positive regulation of cytokine production involved in immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Scimp-deficient bone-marrow-derived dendritic cells show reduced late-phase (beyond 24 h) cytokine production after Dectin-1 stimulation with zymosan (PMID:27288407). Reason: The knockout phenotype is real but restricted to sustained late-phase responses downstream of Dectin-1; early responses were normal. The best-established cytokine function of SCIMP is the TLR-driven IL-6/IL-12p40 output in macrophages, captured by the specific IL-6 and IL-12 production terms. Supporting Evidence: PMID:27288407 Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 |
| GO:0002732 positive regulation of dendritic cell cytokine production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Based on reduced late-phase cytokine production by Scimp-/- BMDCs after Dectin-1 stimulation (PMID:27288407). Reason: Supported by the mouse knockout in dendritic cells, but a modest, late-phase, Dectin-1-specific contribution rather than the core role. Supporting Evidence: PMID:27288407 Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 |
| GO:0002732 positive regulation of dendritic cell cytokine production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Based on reduced late-phase cytokine production by Scimp-/- BMDCs after Dectin-1 stimulation (PMID:27288407). Reason: Supported by the mouse knockout in dendritic cells, but a modest, late-phase, Dectin-1-specific contribution rather than the core role. Supporting Evidence: PMID:27288407 Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | MODIFY | Summary: Binary interaction of SCIMP with LYN. Reason: The interaction with LYN is real and functionally important (SCIMP constitutively scaffolds the Src-family kinase), but bare protein binding is uninformative. The SCIMP proline-rich region binds the LYN SH3 domain, so SH3 domain binding is the informative replacement. Proposed replacements: SH3 domain binding Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Interacts (via proline-rich region) with LYN (via SH3 domain) PMID:21930792 In B cells, it is constitutively associated with Lyn kinase and becomes tyrosine phosphorylated after major histocompatibility complex type II (MHC-II) stimulation. |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | REMOVE | Summary: Binary interaction of SCIMP with tetraspanin CD37. Reason: SCIMP associates with tetraspanin CD37 in tetraspanin-enriched microdomains (captured by the tetraspanin-enriched microdomain CC annotation). The association reflects co-residence in a membrane microdomain rather than an informative molecular function, so bare protein binding is removed; this does not mean the association is false. Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Interacts with CD37, CD53 and CD81 (PubMed:21930792). |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | REMOVE | Summary: Binary interaction of SCIMP with tetraspanin CD53. Reason: SCIMP associates with tetraspanin CD53 in tetraspanin-enriched microdomains (captured by the tetraspanin-enriched microdomain CC annotation). The association reflects co-residence in a membrane microdomain rather than an informative molecular function, so bare protein binding is removed; this does not mean the association is false. Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Interacts with CD37, CD53 and CD81 (PubMed:21930792). |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | MODIFY | Summary: Binary interaction of SCIMP with CSK. Reason: Phospho-tyrosine sites in SCIMP recruit the SH2 domain of CSK; bare protein binding is uninformative, so SH2 domain binding is the informative replacement. Proposed replacements: SH2 domain binding Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Interacts with CSK (via SH2 domain); this interaction is dependent on phosphorylation of Tyr-107 (PubMed:21930792). PMID:21930792 When phosphorylated, SCIMP binds to the SLP65 adaptor protein and also to the inhibitory kinase Csk. |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | REMOVE | Summary: Binary interaction of SCIMP with tetraspanin CD81. Reason: SCIMP associates with tetraspanin CD81 in tetraspanin-enriched microdomains (captured by the tetraspanin-enriched microdomain CC annotation). The association reflects co-residence in a membrane microdomain rather than an informative molecular function, so bare protein binding is removed; this does not mean the association is false. Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Interacts with CD37, CD53 and CD81 (PubMed:21930792). |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | MODIFY | Summary: Binary interaction of SCIMP with GRB2. Reason: Phospho-tyrosine sites in SCIMP recruit the SH2 domain of GRB2; bare protein binding is uninformative, so SH2 domain binding is the informative replacement. Proposed replacements: SH2 domain binding Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Interacts with GRB2 (via SH2 domain); this interaction may be dependent on phosphorylation of Tyr-69 (By similarity). |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | REMOVE | Summary: Binary interaction of SCIMP with CCDC81. Reason: Interaction with the coiled-coil protein CCDC81 has no described functional context for SCIMP (the cited abstract does not mention it; IntAct records mostly come from binary screens). Bare protein binding is uninformative and is removed; removal does not assert the interaction is false. |
| GO:0005515 protein binding | IPI PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | MODIFY | Summary: Binary interaction of SCIMP with BLNK (SLP65). Reason: Phospho-tyrosine sites in SCIMP recruit the SH2 domain of BLNK (SLP65); bare protein binding is uninformative, so SH2 domain binding is the informative replacement. Proposed replacements: SH2 domain binding Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Interacts with BLNK (via SH2 domain); this interaction is dependent on phosphorylation of Tyr-131 (PubMed:21930792). PMID:21930792 When phosphorylated, SCIMP binds to the SLP65 adaptor protein and also to the inhibitory kinase Csk. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Binary interaction of SCIMP with MEOX2. Reason: High-throughput binary yeast two-hybrid hit (HuRI) with a nuclear homeobox transcription factor; no biological context links it to a palmitoylated plasma membrane adaptor. Bare protein binding is uninformative and is removed; removal does not assert the interaction is false. |
| GO:0005886 plasma membrane | EXP PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | ACCEPT | Summary: SCIMP is a palmitoylated single-pass type III transmembrane adaptor localized at the plasma membrane in B cells, dendritic cells and macrophages (PMID:21930792, PMID:28098138). Reason: Plasma membrane is the core location for a transmembrane adaptor protein (TRAP) family member that recruits cytosolic effectors to the membrane. Supporting Evidence: PMID:21930792 Here we report the discovery of a new palmitoylated transmembrane adaptor protein, termed SCIMP. file:human/SCIMP/SCIMP-uniprot.txt Cell membrane {ECO:0000269|PubMed:21930792}; Lipid-anchor {ECO:0000269|PubMed:21930792}. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SCIMP is a palmitoylated single-pass type III transmembrane adaptor localized at the plasma membrane in B cells, dendritic cells and macrophages (PMID:21930792, PMID:28098138). Reason: Plasma membrane is the core location for a transmembrane adaptor protein (TRAP) family member that recruits cytosolic effectors to the membrane. Supporting Evidence: PMID:21930792 Here we report the discovery of a new palmitoylated transmembrane adaptor protein, termed SCIMP. file:human/SCIMP/SCIMP-uniprot.txt Cell membrane {ECO:0000269|PubMed:21930792}; Lipid-anchor {ECO:0000269|PubMed:21930792}. |
| GO:0016020 membrane | IDA PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | MODIFY | Summary: SCIMP is an integral membrane protein (palmitoylated TRAP). Reason: Correct but less specific than the evidence: SCIMP is at the plasma membrane (also annotated here). Replace with plasma membrane. Proposed replacements: plasma membrane Supporting Evidence: PMID:21930792 Here we report the discovery of a new palmitoylated transmembrane adaptor protein, termed SCIMP. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: SCIMP is an integral membrane protein (palmitoylated TRAP). Reason: Correct but less specific than the evidence: SCIMP is at the plasma membrane (also annotated here). Replace with plasma membrane. Proposed replacements: plasma membrane Supporting Evidence: PMID:21930792 Here we report the discovery of a new palmitoylated transmembrane adaptor protein, termed SCIMP. |
| GO:0030175 filopodium | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Full-length SCIMP is concentrated in filopodia and ruffles of macrophages (PMID:28098138). Reason: Supported by microscopy in mouse macrophages; one of several plasma membrane projections occupied by SCIMP and not specifically linked to function, so non-core. Supporting Evidence: PMID:28098138 SCIMP staining was apparent on intracellular punctate membranes, but was particularly prominent on the macrophage plasma membrane, where it was further concentrated in cell surface projections, notably the filopodia and ruffles of some cells. |
| GO:0030175 filopodium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Full-length SCIMP is concentrated in filopodia and ruffles of macrophages (PMID:28098138). Reason: Supported by microscopy in mouse macrophages; one of several plasma membrane projections occupied by SCIMP and not specifically linked to function, so non-core. Supporting Evidence: PMID:28098138 SCIMP staining was apparent on intracellular punctate membranes, but was particularly prominent on the macrophage plasma membrane, where it was further concentrated in cell surface projections, notably the filopodia and ruffles of some cells. |
| GO:0031256 leading edge membrane | IDA PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | KEEP AS NON CORE | Summary: SCIMP is present at the leading edge of migrating cells (PMID:21930792). Reason: Localization reported in the original human characterization; a peripheral observation not tied to SCIMP function. Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Present at regions of cell-cell contacts but also at the leading edge of migrating cells (PubMed:21930792). |
| GO:0031259 uropod membrane | IDA PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | KEEP AS NON CORE | Summary: SCIMP colocalizes with tetraspanins CD37, CD53 and CD81 at the uropod (PMID:21930792). Reason: Follows from its association with tetraspanin-enriched microdomains; peripheral to function. Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt Colocalized with tetraspanins CD37, CD53, and CD81 at the uropod (PubMed:21930792). |
| GO:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: SCIMP binds the TLR4 TIR domain after LPS stimulation, scaffolds Lyn, Syk and Erk1/2 to phosphorylate TLR4 and drive a selective proinflammatory (IL-6, IL-12p40) programme (PMID:28098138, PMID:35337798, PMID:34496234). Reason: Core role. The IBA node (PTN000948237) is seeded by the mouse experimental annotation; the human ortholog is within the same immune-restricted clade and human THP-1 work (PMID:35337798) and the conserved human TLR4 Y674 (PMID:37058370) support conservation. Supporting Evidence: PMID:28098138 SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. |
| GO:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: SCIMP binds the TLR4 TIR domain after LPS stimulation, scaffolds Lyn, Syk and Erk1/2 to phosphorylate TLR4 and drive a selective proinflammatory (IL-6, IL-12p40) programme (PMID:28098138, PMID:35337798, PMID:34496234). Reason: Core role. The IBA node (PTN000948237) is seeded by the mouse experimental annotation; the human ortholog is within the same immune-restricted clade and human THP-1 work (PMID:35337798) and the conserved human TLR4 Y674 (PMID:37058370) support conservation. Supporting Evidence: PMID:28098138 SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. |
| GO:0031666 positive regulation of lipopolysaccharide-mediated signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: SCIMP binds the TLR4 TIR domain after LPS stimulation, scaffolds Lyn, Syk and Erk1/2 to phosphorylate TLR4 and drive a selective proinflammatory (IL-6, IL-12p40) programme (PMID:28098138, PMID:35337798, PMID:34496234). Reason: Core role. The IBA node (PTN000948237) is seeded by the mouse experimental annotation; the human ortholog is within the same immune-restricted clade and human THP-1 work (PMID:35337798) and the conserved human TLR4 Y674 (PMID:37058370) support conservation. Supporting Evidence: PMID:28098138 SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. |
| GO:0032735 positive regulation of interleukin-12 production | IEA GO_REF:0000107 | ACCEPT | Summary: SCIMP knockdown in mouse macrophages reduces TLR-inducible IL-12p40, and overexpression selectively amplifies LPS-induced IL-12p40 (PMID:28098138). Reason: Selective cytokine output is the defining functional consequence of SCIMP in TLR signalling. Supporting Evidence: PMID:28098138 Indeed, after depletion of SCIMP with two specific siRNAs, the synthesis and secretion of the proinflammatory cytokines interleukin 6 (IL-6) and IL-12p40 are substantially reduced, while remarkably, tumor necrosis factor (TNF) is unaffected PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. |
| GO:0032735 positive regulation of interleukin-12 production | ISS GO_REF:0000024 | ACCEPT | Summary: SCIMP knockdown in mouse macrophages reduces TLR-inducible IL-12p40, and overexpression selectively amplifies LPS-induced IL-12p40 (PMID:28098138). Reason: Selective cytokine output is the defining functional consequence of SCIMP in TLR signalling. Supporting Evidence: PMID:28098138 Indeed, after depletion of SCIMP with two specific siRNAs, the synthesis and secretion of the proinflammatory cytokines interleukin 6 (IL-6) and IL-12p40 are substantially reduced, while remarkably, tumor necrosis factor (TNF) is unaffected PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | ACCEPT | Summary: SCIMP knockdown in mouse macrophages reduces TLR-inducible IL-6 synthesis and secretion without affecting TNF (PMID:28098138). Reason: Selective cytokine output is the defining functional consequence of SCIMP in TLR signalling. Supporting Evidence: PMID:28098138 Indeed, after depletion of SCIMP with two specific siRNAs, the synthesis and secretion of the proinflammatory cytokines interleukin 6 (IL-6) and IL-12p40 are substantially reduced, while remarkably, tumor necrosis factor (TNF) is unaffected PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. |
| GO:0032755 positive regulation of interleukin-6 production | ISS GO_REF:0000024 | ACCEPT | Summary: SCIMP knockdown in mouse macrophages reduces TLR-inducible IL-6 synthesis and secretion without affecting TNF (PMID:28098138). Reason: Selective cytokine output is the defining functional consequence of SCIMP in TLR signalling. Supporting Evidence: PMID:28098138 Indeed, after depletion of SCIMP with two specific siRNAs, the synthesis and secretion of the proinflammatory cytokines interleukin 6 (IL-6) and IL-12p40 are substantially reduced, while remarkably, tumor necrosis factor (TNF) is unaffected PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. |
| GO:0032874 positive regulation of stress-activated MAPK cascade | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Scimp-/- BMDCs show reduced sustained p38 and JNK phosphorylation after Dectin-1 stimulation (PMID:27288407); SCIMP knockdown also impairs LPS-induced p38/JNK phosphorylation in macrophages (PMID:28098138). Reason: Supported by knockout and knockdown, but SCIMP's best-characterized MAPK role is as an Erk1/2 scaffold (positive regulation of ERK1 and ERK2 cascade); p38/JNK effects are secondary. Supporting Evidence: PMID:27288407 Consistent with the long-lasting SCIMP phosphorylation, we observed a significant reduction of ERK and p38 phosphorylation in SCIMP-deficient BMDCs at this late time point PMID:27288407 Similar results were also obtained for p38 and JNK MAP kinases |
| GO:0032874 positive regulation of stress-activated MAPK cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Scimp-/- BMDCs show reduced sustained p38 and JNK phosphorylation after Dectin-1 stimulation (PMID:27288407); SCIMP knockdown also impairs LPS-induced p38/JNK phosphorylation in macrophages (PMID:28098138). Reason: Supported by knockout and knockdown, but SCIMP's best-characterized MAPK role is as an Erk1/2 scaffold (positive regulation of ERK1 and ERK2 cascade); p38/JNK effects are secondary. Supporting Evidence: PMID:27288407 Consistent with the long-lasting SCIMP phosphorylation, we observed a significant reduction of ERK and p38 phosphorylation in SCIMP-deficient BMDCs at this late time point PMID:27288407 Similar results were also obtained for p38 and JNK MAP kinases |
| GO:0034138 toll-like receptor 3 signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCIMP silencing reduces IL-6 and IL-12p40 induced by poly(I:C) (TLR3) in mouse macrophages (PMID:28098138). Reason: Supported only by supplementary siRNA cytokine data; SCIMP is not shown to bind or be phosphorylated downstream of TLR3, so this is retained as non-core relative to the well-characterized TLR4 role. Supporting Evidence: PMID:28098138 siRNA silencing of SCIMP in BMM reduced the inducible production of IL-6 and IL-12p40, but not TNF, in response to agonists of TLR3 (Poly(I:C)), TLR7 (imiquimod) and TLR1/2 (Pam3CSK4) |
| GO:0034138 toll-like receptor 3 signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCIMP silencing reduces IL-6 and IL-12p40 induced by poly(I:C) (TLR3) in mouse macrophages (PMID:28098138). Reason: Supported only by supplementary siRNA cytokine data; SCIMP is not shown to bind or be phosphorylated downstream of TLR3, so this is retained as non-core relative to the well-characterized TLR4 role. Supporting Evidence: PMID:28098138 siRNA silencing of SCIMP in BMM reduced the inducible production of IL-6 and IL-12p40, but not TNF, in response to agonists of TLR3 (Poly(I:C)), TLR7 (imiquimod) and TLR1/2 (Pam3CSK4) |
| GO:0034142 toll-like receptor 4 signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: SCIMP binds TLR4-TIR upon LPS stimulation, is required for TLR4 tyrosine phosphorylation and for LPS-induced IL-6/IL-12p40 production (PMID:28098138); it also scaffolds Syk and Erk1/2 to TLR4 (PMID:35337798, PMID:34496234). Reason: Core process: SCIMP acts as a non-TIR adaptor within the TLR4 pathway. Supporting Evidence: PMID:28098138 SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. PMID:28098138 In addition, TLR4 co-immunoprecipitated with SCIMP, and in this case, the interaction was strictly LPS-induced PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:34496234 SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production |
| GO:0034142 toll-like receptor 4 signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: SCIMP binds TLR4-TIR upon LPS stimulation, is required for TLR4 tyrosine phosphorylation and for LPS-induced IL-6/IL-12p40 production (PMID:28098138); it also scaffolds Syk and Erk1/2 to TLR4 (PMID:35337798, PMID:34496234). Reason: Core process: SCIMP acts as a non-TIR adaptor within the TLR4 pathway. Supporting Evidence: PMID:28098138 SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. PMID:28098138 In addition, TLR4 co-immunoprecipitated with SCIMP, and in this case, the interaction was strictly LPS-induced PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:34496234 SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production |
| GO:0034154 toll-like receptor 7 signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCIMP silencing reduces IL-6 and IL-12p40 induced by imiquimod (TLR7) in mouse macrophages (PMID:28098138). Reason: Supplementary siRNA cytokine data only; non-core relative to TLR4. Supporting Evidence: PMID:28098138 siRNA silencing of SCIMP in BMM reduced the inducible production of IL-6 and IL-12p40, but not TNF, in response to agonists of TLR3 (Poly(I:C)), TLR7 (imiquimod) and TLR1/2 (Pam3CSK4) |
| GO:0034154 toll-like receptor 7 signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCIMP silencing reduces IL-6 and IL-12p40 induced by imiquimod (TLR7) in mouse macrophages (PMID:28098138). Reason: Supplementary siRNA cytokine data only; non-core relative to TLR4. Supporting Evidence: PMID:28098138 siRNA silencing of SCIMP in BMM reduced the inducible production of IL-6 and IL-12p40, but not TNF, in response to agonists of TLR3 (Poly(I:C)), TLR7 (imiquimod) and TLR1/2 (Pam3CSK4) |
| GO:0038123 toll-like receptor TLR1:TLR2 signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCIMP silencing reduces Pam3CSK4 (TLR1/2)-induced IL-6/IL-12p40; SCIMP is rapidly phosphorylated after Pam3CSK4 and co-immunoprecipitates with activated TLR2 (PMID:28098138, PMID:35337798). Reason: Reasonably supported (cytokine knockdown plus physical association with TLR2), but secondary to the TLR4 role. Supporting Evidence: PMID:28098138 siRNA silencing of SCIMP in BMM reduced the inducible production of IL-6 and IL-12p40, but not TNF, in response to agonists of TLR3 (Poly(I:C)), TLR7 (imiquimod) and TLR1/2 (Pam3CSK4) PMID:35337798 Activated TLR2 and TLR4 were each coimmunoprecipitated with SCIMP |
| GO:0038123 toll-like receptor TLR1:TLR2 signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCIMP silencing reduces Pam3CSK4 (TLR1/2)-induced IL-6/IL-12p40; SCIMP is rapidly phosphorylated after Pam3CSK4 and co-immunoprecipitates with activated TLR2 (PMID:28098138, PMID:35337798). Reason: Reasonably supported (cytokine knockdown plus physical association with TLR2), but secondary to the TLR4 role. Supporting Evidence: PMID:28098138 siRNA silencing of SCIMP in BMM reduced the inducible production of IL-6 and IL-12p40, but not TNF, in response to agonists of TLR3 (Poly(I:C)), TLR7 (imiquimod) and TLR1/2 (Pam3CSK4) PMID:35337798 Activated TLR2 and TLR4 were each coimmunoprecipitated with SCIMP |
| GO:0043235 signaling receptor complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCIMP co-immunoprecipitates with TLR4 in an LPS-inducible manner (PMID:28098138). Reason: An inducible SCIMP-TLR4 assembly with LYN and SYK is directly observed by co-immunoprecipitation after LPS stimulation. It is a transient adaptor-receptor association rather than a stable complex, so it is kept as non-core; no more specific complex term exists. Supporting Evidence: PMID:28098138 In addition, TLR4 co-immunoprecipitated with SCIMP, and in this case, the interaction was strictly LPS-induced PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. |
| GO:0043235 signaling receptor complex | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCIMP co-immunoprecipitates with TLR4 in an LPS-inducible manner (PMID:28098138). Reason: An inducible SCIMP-TLR4 assembly with LYN and SYK is directly observed by co-immunoprecipitation after LPS stimulation. It is a transient adaptor-receptor association rather than a stable complex, so it is kept as non-core; no more specific complex term exists. Supporting Evidence: PMID:28098138 In addition, TLR4 co-immunoprecipitated with SCIMP, and in this case, the interaction was strictly LPS-induced PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. |
| GO:0045335 phagocytic vesicle | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: SCIMP localizes to zymosan-containing phagosomes in dendritic cells (PMID:27288407). Reason: Observed in mouse BMDCs after particulate beta-glucan exposure; a stimulus-dependent location. Supporting Evidence: PMID:27288407 Moreover, SCIMP localized into zymosan-containing phagosomes and remained there for at least 30 min |
| GO:0045335 phagocytic vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCIMP localizes to zymosan-containing phagosomes in dendritic cells (PMID:27288407). Reason: Observed in mouse BMDCs after particulate beta-glucan exposure; a stimulus-dependent location. Supporting Evidence: PMID:27288407 Moreover, SCIMP localized into zymosan-containing phagosomes and remained there for at least 30 min |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | MODIFY | Summary: SCIMP is a transmembrane adaptor that scaffolds Lyn, Syk, Erk1/2, Grb2, SLP65/SLP76 and Csk to TLR4 and other receptors (PMID:28098138, PMID:35337798, PMID:34496234, PMID:21930792). Reason: The adaptor function is correct and core, but SCIMP specifically assembles kinases and effectors within signalling pathways; signaling adaptor activity (GO:0035591, a descendant via protein-macromolecule adaptor activity) is the precise term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000948237 SUPPORTS TRANSFER The SCIMP-clade node is soundly placed (seeded by mouse Scimp experimental data); only the term is broader than the signaling adaptor activity the evidence supports. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. PMID:34496234 SCIMP is a direct scaffold for Erk1/2 in TLR pathways |
| GO:0060090 molecular adaptor activity | IEA GO_REF:0000107 | MODIFY | Summary: SCIMP is a transmembrane adaptor that scaffolds Lyn, Syk, Erk1/2, Grb2, SLP65/SLP76 and Csk to TLR4 and other receptors (PMID:28098138, PMID:35337798, PMID:34496234, PMID:21930792). Reason: The adaptor function is correct and core, but SCIMP specifically assembles kinases and effectors within signalling pathways; signaling adaptor activity (GO:0035591, a descendant via protein-macromolecule adaptor activity) is the precise term. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. PMID:34496234 SCIMP is a direct scaffold for Erk1/2 in TLR pathways |
| GO:0060090 molecular adaptor activity | ISS GO_REF:0000024 | MODIFY | Summary: SCIMP is a transmembrane adaptor that scaffolds Lyn, Syk, Erk1/2, Grb2, SLP65/SLP76 and Csk to TLR4 and other receptors (PMID:28098138, PMID:35337798, PMID:34496234, PMID:21930792). Reason: The adaptor function is correct and core, but SCIMP specifically assembles kinases and effectors within signalling pathways; signaling adaptor activity (GO:0035591, a descendant via protein-macromolecule adaptor activity) is the precise term. Proposed replacements: signaling adaptor activity Supporting Evidence: PMID:28098138 In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. PMID:35337798 Here, we show that SCIMP recruits Syk in response to lipopolysaccharide-mediated TLR4 activation. PMID:34496234 SCIMP is a direct scaffold for Erk1/2 in TLR pathways |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IDA PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | ACCEPT | Summary: shRNA knockdown in the K46 B cell line reduced MHC-II-induced ERK activation (PMID:21930792); in macrophages SCIMP is a direct membrane scaffold for Erk1/2 downstream of TLR4 (PMID:34496234), and in BMDCs it sustains late ERK activation after Dectin-1 (PMID:27288407). Reason: Consistent across three systems. Note that primary Scimp-/- B cells did not show the MHC-II ERK defect (PMID:27288407), but the TLR4/Erk1/2 scaffold role in macrophages is strong. Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt enhancing ERK activity upon MHC-II stimulation (PubMed:21930792) PMID:34496234 SCIMP is a direct scaffold for Erk1/2 in TLR pathways PMID:34496234 SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IEA GO_REF:0000107 | ACCEPT | Summary: shRNA knockdown in the K46 B cell line reduced MHC-II-induced ERK activation (PMID:21930792); in macrophages SCIMP is a direct membrane scaffold for Erk1/2 downstream of TLR4 (PMID:34496234), and in BMDCs it sustains late ERK activation after Dectin-1 (PMID:27288407). Reason: Consistent across three systems. Note that primary Scimp-/- B cells did not show the MHC-II ERK defect (PMID:27288407), but the TLR4/Erk1/2 scaffold role in macrophages is strong. Supporting Evidence: file:human/SCIMP/SCIMP-uniprot.txt enhancing ERK activity upon MHC-II stimulation (PubMed:21930792) PMID:34496234 SCIMP is a direct scaffold for Erk1/2 in TLR pathways PMID:34496234 SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production |
| GO:0071226 cellular response to molecule of fungal origin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SCIMP is phosphorylated after Dectin-1 stimulation by zymosan and sustains late MAPK signalling and cytokine output in BMDCs (PMID:27288407). Reason: True but broad; SCIMP participates in Dectin-1 (stimulatory C-type lectin receptor) signalling, a peripheral role relative to TLR adaptor function. Supporting Evidence: PMID:27288407 SCIMP is strongly phosphorylated after Dectin-1 stimulation and that it participates in signal transduction downstream of this important pattern recognition receptor. PMID:27288407 Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 |
| GO:0071226 cellular response to molecule of fungal origin | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SCIMP is phosphorylated after Dectin-1 stimulation by zymosan and sustains late MAPK signalling and cytokine output in BMDCs (PMID:27288407). Reason: True but broad; SCIMP participates in Dectin-1 (stimulatory C-type lectin receptor) signalling, a peripheral role relative to TLR adaptor function. Supporting Evidence: PMID:27288407 SCIMP is strongly phosphorylated after Dectin-1 stimulation and that it participates in signal transduction downstream of this important pattern recognition receptor. PMID:27288407 Our analysis of SCIMP-deficient dendritic cells revealed that SCIMP specifically contributes to sustaining long-term MAP kinase signaling and cytokine production downstream of Dectin-1 |
| GO:0097197 tetraspanin-enriched microdomain | IDA PMID:21930792 SCIMP, a transmembrane adaptor protein involved in major his... | ACCEPT | Summary: SCIMP associates with tetraspanin-enriched microdomains (with CD37, CD53, CD81) together with MHC-II (PMID:21930792). Reason: Defining membrane-domain location of SCIMP; also captured by the InterPro (IPR028181) family mapping. Supporting Evidence: PMID:21930792 SCIMP is expressed in B cells and other professional APCs and is localized in the immunological synapse due to its association with tetraspanin-enriched microdomains. file:human/SCIMP/SCIMP-uniprot.txt Interacts with CD37, CD53 and CD81 (PubMed:21930792). |
| GO:0097197 tetraspanin-enriched microdomain | IEA GO_REF:0000002 | ACCEPT | Summary: SCIMP associates with tetraspanin-enriched microdomains (with CD37, CD53, CD81) together with MHC-II (PMID:21930792). Reason: Defining membrane-domain location of SCIMP; also captured by the InterPro (IPR028181) family mapping. Supporting Evidence: PMID:21930792 SCIMP is expressed in B cells and other professional APCs and is localized in the immunological synapse due to its association with tetraspanin-enriched microdomains. file:human/SCIMP/SCIMP-uniprot.txt Interacts with CD37, CD53 and CD81 (PubMed:21930792). |
| GO:0035662 Toll-like receptor 4 binding | ISS GO_REF:0000024 | NEW | Summary: SCIMP binds the TIR domain of TLR4 after LPS stimulation; shown for the mouse ortholog by co-immunoprecipitation and binding-site mutagenesis (PMID:28098138). Reason: The TLR4 interaction is the basis of SCIMP's core adaptor role and is asserted in the core function, but human SCIMP has no GOA row for it. There is no direct human binding experiment (the human THP-1 work in PMID:35337798 shows SCIMP-SYK, not SCIMP-TLR4, co-immunoprecipitation), so the annotation is proposed by sequence similarity to mouse Scimp, consistent with the UniProt human entry (By similarity) and with the conserved human TLR4 Y674 phosphorylation site (PMID:37058370). Supporting Evidence: PMID:28098138 SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. file:human/SCIMP/SCIMP-uniprot.txt Interacts with TLR4; this interaction occurs upon lipopolysaccharide activation of TLR4 and is enhanced by phosphorylation of Tyr-107 by LYN (By similarity). |
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Download this section (compressed HTML)Q: SCIMP is required for selective TLR-induced IL-6/IL-12p40 but not TNF; which downstream branch (ERK/c-FOS via TLR4 Y672, or another) explains this selectivity, and is it conserved in human macrophages?
Q: Is the MHC-II reverse-signalling role seen in the K46 B cell line physiologically relevant, given that primary Scimp-/- B cells showed no ERK defect?
Q: Does the exosome-secreted SCIMP N-terminal peptide acting as an FPR1/2 neutrophil chemoattractant (PMID:38263143) represent a genuine extracellular function warranting GO annotation, given that SCIMP is otherwise a transmembrane adaptor?
Experiment: CRISPR-knockout SCIMP in human monocyte-derived macrophages and measure LPS-induced TLR4 Y674 phosphorylation, ERK recruitment and the cytokine profile, with rescue by wild-type or Y107F/Y131F SCIMP (human numbering; mouse Y96/Y120).
Hypothesis: Human SCIMP scaffolds LYN/SYK/ERK to TLR4 and selectively drives IL-6/IL-12p40 in primary human macrophages as it does in mouse.
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