{"gene":"CAMLG","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1997,"finding":"CAML acts as a signaling intermediate downstream of TACI (a TNF receptor superfamily member). Cross-linking of TACI activated NF-AT, AP-1, and NF-κB transcription factors, and a dominant-negative CAML mutant specifically blocked TACI-induced NF-AT activation, placing CAML in the TACI signaling pathway.","method":"Dominant-negative mutant transfection, transcriptional reporter assays, antibody cross-linking in Jurkat T cells","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative functional assay with reporter readout, single lab, two orthogonal approaches (overexpression + dominant-negative block)","pmids":["9311921"],"is_preprint":false},{"year":2003,"finding":"CAML is required for recycling of internalized EGF receptor (EGFR) back to the plasma membrane. CAML-deficient cells show normal EGFR internalization and EGF-induced signaling but defective receptor recycling and reduced surface EGFR accumulation. CAML directly associates with the kinase domain of EGFR in a ligand-dependent manner.","method":"CAML gene knockout (mouse embryonic fibroblasts), EGF receptor trafficking assays (surface accumulation, internalization, recycling), co-immunoprecipitation","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype plus direct binding assay, multiple orthogonal methods in one rigorous study","pmids":["12919676"],"is_preprint":false},{"year":2005,"finding":"CAML interacts with ATRAP (AT1 receptor-associated protein) via its N-terminal hydrophilic domain (aa 1–189) and functions as a signal transducer for angiotensin II-mediated NFAT activation. ATRAP overexpression decreased CAML/Ang II-induced NFAT activation, while ATRAP knockdown increased NFAT activity; the CAML N-terminal domain (aa 1–189) sensitized NFAT activation in response to Ang II. The CAML–ATRAP interaction localizes to ER vesicular structures.","method":"Yeast two-hybrid, co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), immunofluorescence colocalization, RNA interference, transcriptional reporter assays in HEK293 cells","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (yeast 2-hybrid, co-IP, BRET, reporter assays, RNAi) in single lab study","pmids":["15668245"],"is_preprint":false},{"year":2005,"finding":"CAML interacts with p56Lck and regulates its subcellular localization in resting and TCR-stimulated thymocytes. CAML-deficient thymocytes show enhanced p56Lck and ZAP-70 phosphorylation and increased IL-2 production and cell death after TCR stimulation, indicating CAML acts as a negative regulator of p56Lck signaling. CAML is essential for positive selection and suppression of negative selection during thymopoiesis.","method":"Conditional CAML knockout in mouse thymocytes, co-immunoprecipitation, kinase phosphorylation assays, IL-2 production assays, flow cytometry of thymocyte populations","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined developmental phenotype plus direct binding and signaling assays, multiple orthogonal methods","pmids":["16111633"],"is_preprint":false},{"year":2005,"finding":"The intracellular C-terminus of fibrocystin (ARPKD protein) directly interacts with CAML. Both proteins co-localize in the apical membrane, primary cilia, and basal body of distal nephron cells.","method":"Yeast two-hybrid screen, co-immunoprecipitation from COS7 cells, immunofluorescence colocalization","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single co-IP confirmation of yeast 2-hybrid hit without functional follow-up on CAML mechanism","pmids":["16243292"],"is_preprint":false},{"year":2009,"finding":"CAML loss causes anaphase failure and chromosome missegregation. CAML-deficient MEFs fail to segregate chromosomes in anaphase (a 'cut' phenotype), have spindle dysfunction, lagging/misaligned chromosomes and chromatin bridges, a modestly weakened spindle assembly checkpoint (SAC), and increased aneuploidy. CAML functions as a regulator of mitotic spindle function and a modulator of SAC maintenance.","method":"Cre-loxP conditional knockout MEFs, live-cell imaging, spindle assembly checkpoint assays, aneuploidy measurement by cytogenetics","journal":"Cell Cycle","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined mitotic phenotype across multiple readouts (imaging, SAC assay, aneuploidy) in single study","pmids":["19229138"],"is_preprint":false},{"year":2010,"finding":"CAML-deficient thymocytes accumulate high levels of reactive oxygen species (ROS) and undergo accelerated apoptosis. Genetic removal of the pro-apoptotic BH3-only protein Bim (but not deletion of p53 or Fas) significantly rescued survival of CAML-deficient thymocytes, placing CAML upstream of Bim-dependent apoptosis in thymocyte survival.","method":"Conditional knockout, genetic epistasis (CAML KO × Bim KO double mutant mice), ROS measurement, in vitro apoptosis assays","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double-mutant rescue provides clear pathway placement, multiple death stimuli tested","pmids":["20300112"],"is_preprint":false},{"year":2010,"finding":"CAML interacts with TMUB1 (C7orf21/HOPS). The interaction was identified by yeast two-hybrid screen of a brain library and confirmed by co-immunoprecipitation in HEK cells. Both proteins co-localize in the cytoplasm.","method":"Yeast two-hybrid, co-immunoprecipitation in HEK cells, immunofluorescence colocalization","journal":"PloS One","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single co-IP confirmation without further mechanistic dissection of CAML function","pmids":["20582322"],"is_preprint":false},{"year":2010,"finding":"CAML does not contribute to tetherin-mediated restriction of HIV-1 particle release. Stable depletion of CAML in HeLa cells had no effect on cell-surface tetherin levels and did not relieve tetherin-mediated restriction.","method":"Stable shRNA knockdown of CAML, flow cytometry for tetherin surface levels, HIV particle release assays","journal":"PloS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean stable knockdown with multiple functional readouts; negative result robustly established","pmids":["20126395"],"is_preprint":false},{"year":2010,"finding":"CAML is required for prolactin receptor (PRLR) signaling. CAML associates with PRLR and this interaction is augmented by PRL stimulation. CAML silencing impairs PRLR-dependent Stat5 and Mek1/2 activation, PRL internalization with cyclophilin B, PRLR recycling, and Ca2+ mobilization, thereby reducing PRL-dependent proliferation of breast cancer cells.","method":"Co-immunoprecipitation, siRNA silencing, signaling pathway assays (Stat5, Mek1/2 phosphorylation), Ca2+ measurement, receptor recycling assays","journal":"Breast Cancer Research and Treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP binding plus RNAi loss-of-function with multiple signaling readouts, single lab","pmids":["21128111"],"is_preprint":false},{"year":2012,"finding":"CAML is essential for survival of peripheral follicular (Fo) B cells. Conditional deletion of CAML in B cells caused reduced Fo B cell numbers, increased cellular turnover, and increased apoptosis after LPS and IL-4 stimulation, establishing an ongoing anti-apoptotic role for CAML in mature B cells.","method":"Conditional B cell-specific CAML knockout (CD19-Cre), flow cytometry, in vitro apoptosis assays, inducible gene deletion in mature B cells","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional and inducible knockout with multiple functional readouts confirming cell-autonomous survival role","pmids":["22351938"],"is_preprint":false},{"year":2014,"finding":"WRB and CAML together form a functional receptor complex for TRC40 (Get3) at the ER membrane and are both necessary and sufficient for tail-anchored (TA) protein targeting and insertion into the ER. The transmembrane segments of CAML are essential for creating a functional receptor with WRB. Binding parameters of TRC40 to the WRB/CAML receptor were determined. Yeast lacking GET1 and GET2 are functionally complemented by WRB and CAML.","method":"Yeast complementation assay (GET1/GET2 deletion complementation), in vivo TA protein targeting assays, binding affinity measurement (TRC40 to WRB/CAML), domain mutagenesis of CAML transmembrane segments","journal":"PloS One","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic complementation, direct binding quantification, and domain mutagenesis establishing sufficiency and structure-function in one study","pmids":["24392163"],"is_preprint":false},{"year":2017,"finding":"CAML supports survival and mitotic progression in Myc-driven B-cell lymphomas independently of its TA protein insertion function. The C-terminal 111 amino acid region of CAML (encompassing the WRB-binding domain but not the TRC40-interaction domain) was sufficient to rescue survival and growth of CAML-deleted lymphoma cells without restoring TA protein insertion. Cell death was blocked by Bcl-2/Bcl-xL overexpression. Loss of CAML caused G2/M arrest with low phospho-histone H3.","method":"Tamoxifen-inducible conditional knockout in Eμ-Myc lymphoma cells, domain deletion/rescue experiments, cell cycle analysis, Bcl-2/Bcl-xL overexpression rescue, in vivo tumor regression assay","journal":"Cell Death Discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with domain-swap rescue experiments dissecting TA insertion vs. survival function, multiple orthogonal readouts","pmids":["28580168"],"is_preprint":false},{"year":2018,"finding":"CAML interacts with TMUB1 via TMUB1's TM1 hydrophobic domain. TMUB1 overexpression abolishes the interaction between CAML and its downstream binding partner cyclophilin B, thereby reducing intracellular Ca2+ ([Ca2+]i) and inhibiting hepatocyte proliferation. CAML–cyclophilin B interaction acts upstream of calcineurin to regulate Ca2+ signaling during proliferation.","method":"Co-immunoprecipitation in BRL-3A rat hepatocytes, Ca2+ influx measurement, TMUB1 overexpression and knockout, TM1 domain deletion mutant","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain deletion plus functional readouts (Ca2+ and proliferation), single lab","pmids":["29967478"],"is_preprint":false},{"year":2018,"finding":"Classical Swine Fever Virus p7 interacts with CAMLG at the ER membrane, and this interaction is required for p7-mediated calcium permeability at the ER. Mutant p7 forms unable to interact with CAMLG failed to mediate calcium permeability and showed decreased virulence.","method":"Yeast two-hybrid, confocal colocalization in eukaryotic cells with p7 mutants, calcium permeability assays in ER","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast 2-hybrid confirmed by colocalization with mutagenesis plus functional Ca2+ permeability assay, single lab","pmids":["30154321"],"is_preprint":false},{"year":2019,"finding":"WRB is required for the correct topological integration of CAML into the ER membrane. Without sufficient WRB, CAML fails to adopt its correct three-transmembrane-segment topology and instead generates two aberrant topoforms that congregate in ER-associated clusters and are degraded by the proteasome. WRB acts catalytically to assist CAML topogenesis, consistent with WRB being a member of the Oxa1 superfamily.","method":"Topology mapping (CAML topology determination), WRB knockdown/depletion, proteasome inhibitor treatment, immunofluorescence of aberrant CAML clusters, cell fractionation","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct topology determination combined with WRB depletion and proteasome inhibition, multiple orthogonal methods in single rigorous study","pmids":["31417168"],"is_preprint":false},{"year":2022,"finding":"Loss of functional CAML (via homozygous splice variant c.633+4A>G) causes mislocalization of syntaxin-5 and drastic reduction of Bet1L (v-SNARE) in patient fibroblasts and siCAMLG-depleted HeLa cells, indicating CAML (as part of the TRC pathway) is required for proper assembly of Golgi SNARE complexes and correct TA protein insertion. This CAML deficiency causes a congenital disorder of glycosylation (combined O-linked and type II N-linked glycosylation defect).","method":"Patient fibroblast analysis (homozygous splice variant), siRNA knockdown in HeLa cells, Western blot and immunofluorescence of syntaxin-5 and Bet1L, glycosylation biochemical analysis","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human patient genetics confirmed in two independent cellular models (patient fibroblasts + siRNA HeLa), multiple mechanistic readouts","pmids":["35262690"],"is_preprint":false},{"year":2025,"finding":"CAML is required for motor neuron survival and neuromuscular function via its role in the TRC pathway for TA protein insertion. Neuron-specific CAML deletion causes hind limb weakness, paralysis, and loss of spinal motor neuron cell bodies. CAML depletion perturbs intracellular trafficking: aberrant procathepsin D release, defective CD222 retention in the trans-Golgi network, reduced and mislocalized syntaxin-5, dysfunctional lysosomes, and abnormal protein glycosylation. Neuronal deletion of ASNA1 (TRC40/GET3) produces an identical phenotype, confirming the mechanistic link to the TRC pathway.","method":"Neuron-specific conditional knockout (SLICK-H-Cre and synapsin-Cre), global hypomorphic CAML mice, histology of spinal cord, intracellular trafficking assays (procathepsin D secretion, CD222 localization, syntaxin-5 localization), glycosylation analysis, ASNA1 neuronal KO genetic epistasis","journal":"PLoS Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent Cre lines, genetic epistasis with ASNA1 KO, and multiple mechanistic trafficking readouts in single rigorous study","pmids":["39823474"],"is_preprint":false}],"current_model":"CAML (CAMLG) is an ER transmembrane protein that functions as part of the WRB/CAML heteromeric receptor complex to capture TRC40 (ASNA1/GET3) and mediate post-translational insertion of tail-anchored (TA) proteins into the ER membrane; WRB catalytically assists CAML's own three-TM topogenesis, and together they govern Golgi SNARE assembly, intracellular trafficking, and protein glycosylation. In addition to this core TA-insertion role, CAML acts as a signaling scaffold that interacts with p56Lck to negatively regulate TCR signaling and thymocyte selection, promotes EGF and prolactin receptor recycling, transduces TACI- and angiotensin II-induced NF-AT/AP-1/NF-κB activation, regulates mitotic spindle function and the spindle assembly checkpoint, and suppresses Bim-dependent thymocyte apoptosis—with a separable C-terminal domain supporting lymphoma cell survival and mitotic progression independently of TA protein insertion."},"narrative":{"mechanistic_narrative":"CAMLG (CAML) is an ER transmembrane protein that, together with WRB, forms the membrane receptor for TRC40/ASNA1 (GET3) and mediates post-translational insertion of tail-anchored proteins into the ER, with CAML's transmembrane segments being essential for a functional receptor that is both necessary and sufficient to support TA targeting and to complement yeast lacking GET1/GET2 [PMID:24392163]. CAML's own three-transmembrane topology depends catalytically on WRB; without sufficient WRB, CAML mis-integrates into aberrant topoforms that cluster in the ER and are degraded by the proteasome [PMID:31417168]. Through this TRC pathway, CAML governs assembly of Golgi SNAREs—loss of CAML mislocalizes syntaxin-5 and depletes the v-SNARE Bet1L—and is required for correct protein glycosylation and intracellular trafficking, including procathepsin D handling and CD222 retention in the trans-Golgi network [PMID:35262690, PMID:39823474]. Biallelic loss-of-function of CAMLG causes a congenital disorder of glycosylation with combined O-linked and type II N-linked defects [PMID:35262690], and neuron-specific CAML deletion produces motor neuron loss and paralysis phenocopied by neuronal ASNA1 deletion, confirming the shared TRC mechanism [PMID:39823474]. Beyond TA insertion, CAML acts as a signaling and survival scaffold: it associates ligand-dependently with EGFR and the prolactin receptor to promote their recycling and downstream signaling [PMID:12919676, PMID:21128111], binds p56Lck to negatively regulate TCR signaling and control thymocyte selection [PMID:16111633], and is required for thymocyte and follicular B-cell survival by acting upstream of Bim-dependent apoptosis [PMID:20300112, PMID:22351938]. CAML also regulates mitotic spindle function and anaphase chromosome segregation [PMID:19229138], and a separable C-terminal region supports survival and mitotic progression of Myc-driven lymphoma cells independently of TA protein insertion [PMID:28580168].","teleology":[{"year":1997,"claim":"Established CAML as a signaling intermediate by placing it in the TACI pathway, the first functional assignment for the protein.","evidence":"Dominant-negative mutant and transcriptional reporter assays in Jurkat T cells","pmids":["9311921"],"confidence":"Medium","gaps":["Molecular mechanism of how CAML links TACI to NF-AT not resolved","Direct biochemical contact with TACI not demonstrated"]},{"year":2003,"claim":"Showed CAML controls receptor trafficking rather than internalization, defining a recycling role through direct, ligand-dependent association with the EGFR kinase domain.","evidence":"CAML gene knockout MEFs with EGFR trafficking assays and co-immunoprecipitation","pmids":["12919676"],"confidence":"High","gaps":["Structural basis of CAML-EGFR binding unknown","How CAML mechanistically routes receptors to recycling not defined"]},{"year":2005,"claim":"Extended CAML's signaling-scaffold role to angiotensin II via an ATRAP interaction at the ER and to TCR signaling via p56Lck, and tied it to thymocyte selection.","evidence":"Yeast two-hybrid, co-IP, BRET, reporter assays in HEK293; conditional thymocyte knockout with kinase and flow-cytometry readouts; yeast two-hybrid/co-IP for fibrocystin","pmids":["15668245","16111633","16243292"],"confidence":"High","gaps":["The fibrocystin/ciliary interaction (idx 4) is a single co-IP without functional follow-up","How a single ER protein integrates multiple receptor signals mechanistically unresolved"]},{"year":2009,"claim":"Revealed an unexpected mitotic function, showing CAML loss causes anaphase failure, spindle dysfunction and aneuploidy with a weakened spindle assembly checkpoint.","evidence":"Cre-loxP conditional knockout MEFs with live-cell imaging, SAC assays, and cytogenetics","pmids":["19229138"],"confidence":"High","gaps":["Molecular target of CAML at the spindle/SAC not identified","Connection between ER role and mitotic role unclear"]},{"year":2010,"claim":"Placed CAML upstream of Bim-dependent apoptosis as a survival factor in thymocytes and ruled out a role in tetherin-mediated HIV restriction, while adding prolactin receptor signaling/recycling to its trafficking repertoire.","evidence":"CAML×Bim double-knockout epistasis with ROS/apoptosis assays; stable shRNA knockdown with HIV release assays; co-IP and siRNA with PRLR signaling and recycling readouts; yeast two-hybrid/co-IP for TMUB1","pmids":["20300112","20126395","21128111","20582322"],"confidence":"High","gaps":["How CAML restrains Bim/ROS mechanistically not defined","TMUB1 interaction (idx 7) functionally uncharacterized at this stage"]},{"year":2012,"claim":"Demonstrated an ongoing, cell-autonomous anti-apoptotic requirement for CAML in mature follicular B cells, generalizing its survival function beyond development.","evidence":"B cell-specific and inducible conditional knockout with flow cytometry and apoptosis assays","pmids":["22351938"],"confidence":"High","gaps":["Survival pathway in B cells not molecularly mapped","Whether the same Bim axis operates in B cells untested here"]},{"year":2014,"claim":"Defined CAML's core molecular identity, showing WRB/CAML together are necessary and sufficient as the TRC40 receptor for tail-anchored protein insertion at the ER.","evidence":"Yeast GET1/GET2 complementation, in vivo TA targeting, TRC40 binding affinity measurement, and CAML transmembrane mutagenesis","pmids":["24392163"],"confidence":"High","gaps":["Structure of the WRB/CAML/TRC40 complex not determined","Coupling between TA insertion and CAML's signaling roles unresolved"]},{"year":2017,"claim":"Separated CAML's survival/mitotic activity from its insertase function, showing a C-terminal WRB-binding region rescues lymphoma cell survival without restoring TA insertion.","evidence":"Inducible knockout in Eμ-Myc lymphoma with domain-deletion rescue, cell cycle analysis, Bcl-2/Bcl-xL rescue, and in vivo tumor regression","pmids":["28580168"],"confidence":"High","gaps":["The effector engaged by the C-terminal domain to promote survival not identified","How the same domain drives G2/M progression mechanistically unclear"]},{"year":2018,"claim":"Linked CAML to calcium signaling, showing TMUB1 displaces CAML from cyclophilin B to lower intracellular Ca2+, and identified a viral subversion of CAML-dependent ER calcium permeability.","evidence":"Co-IP with domain deletions and Ca2+/proliferation readouts in hepatocytes; yeast two-hybrid, colocalization, and Ca2+ permeability assays with viral p7 mutants","pmids":["29967478","30154321"],"confidence":"Medium","gaps":["Direct CAML-cyclophilin B-calcineurin biochemistry not fully reconstituted","Physiological breadth of CAML calcium control across cell types untested"]},{"year":2019,"claim":"Clarified the biogenesis hierarchy, showing WRB catalytically assists CAML's own three-TM topogenesis and that mis-topologized CAML is proteasomally degraded.","evidence":"CAML topology mapping with WRB depletion, proteasome inhibition, immunofluorescence of aberrant clusters, and fractionation","pmids":["31417168"],"confidence":"High","gaps":["Catalytic mechanism by which WRB drives CAML integration not detailed","Quality-control machinery degrading mis-topologized CAML not identified"]},{"year":2022,"claim":"Connected CAML to human disease, establishing that biallelic CAMLG loss disrupts Golgi SNARE assembly (syntaxin-5, Bet1L) and causes a congenital disorder of glycosylation.","evidence":"Patient fibroblasts with a homozygous splice variant plus siRNA HeLa models, SNARE Western/immunofluorescence, and glycosylation analysis","pmids":["35262690"],"confidence":"High","gaps":["Full spectrum of TA substrates whose mislocalization drives the CDG phenotype not enumerated","Genotype-phenotype relationship across additional patients not established"]},{"year":2025,"claim":"Demonstrated an in vivo TRC-pathway requirement for CAML in motor neuron survival, with ASNA1 deletion phenocopying CAML loss to confirm the mechanism and tie it to trafficking and glycosylation defects.","evidence":"Multiple neuron-specific Cre lines and hypomorphic mice, spinal cord histology, procathepsin D/CD222/syntaxin-5 trafficking assays, glycosylation analysis, and ASNA1 neuronal-KO epistasis","pmids":["39823474"],"confidence":"High","gaps":["Identity of the critical neuronal TA substrate(s) underlying motor neuron loss not pinpointed","Why neurons are particularly vulnerable to TRC-pathway loss not explained"]},{"year":null,"claim":"It remains unresolved how CAML's single core insertase activity mechanistically gives rise to its diverse receptor-recycling, calcium-signaling, anti-apoptotic, and mitotic functions, and whether these reflect distinct TA substrates or insertion-independent activities.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying substrate map linking TA insertion to the signaling/survival phenotypes","No high-resolution structure of the WRB/CAML/TRC40 receptor","Effector mediating the insertion-independent C-terminal survival function unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[11,16,17]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,3,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[11,15]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,11,14,15]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[16,17]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,16,17]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,9,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,10,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,17]}],"complexes":["WRB/CAML TRC40 receptor"],"partners":["WRB","ASNA1","EGFR","PRLR","LCK","ATRAP","TMUB1","PPIB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49069","full_name":"Guided entry of tail-anchored proteins factor CAMLG","aliases":["Calcium signal-modulating cyclophilin ligand"],"length_aa":296,"mass_kda":33.0,"function":"Required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum (PubMed:23041287, PubMed:24392163, PubMed:27226539). Together with GET1/WRB, acts as a membrane receptor for soluble GET3/TRC40, which recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol (PubMed:23041287, PubMed:24392163, PubMed:27226539). Required for the stability of GET1 (PubMed:32187542). Stimulates calcium signaling in T cells through its involvement in elevation of intracellular calcium (PubMed:7522304). Essential for the survival of peripheral follicular B cells (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/P49069/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CAMLG","classification":"Common Essential","n_dependent_lines":559,"n_total_lines":1208,"dependency_fraction":0.46274834437086093},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"VAPA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CAMLG","total_profiled":1310},"omim":[{"mim_id":"620523","title":"RING FINGER PROTEIN 122; RNF122","url":"https://www.omim.org/entry/620523"},{"mim_id":"620201","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIz; CDG2Z","url":"https://www.omim.org/entry/620201"},{"mim_id":"612056","title":"GUIDED ENTRY OF TAIL-ANCHORED PROTEINS FACTOR 4; GET4","url":"https://www.omim.org/entry/612056"},{"mim_id":"608729","title":"ANGIOTENSIN II RECEPTOR-ASSOCIATED PROTEIN; AGTRAP","url":"https://www.omim.org/entry/608729"},{"mim_id":"602698","title":"NUCLEAR FACTOR OF ACTIVATED T CELLS, CYTOPLASMIC, CALCINEURIN-DEPENDENT 3; NFATC3","url":"https://www.omim.org/entry/602698"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CAMLG"},"hgnc":{"alias_symbol":["CAML","GET2"],"prev_symbol":[]},"alphafold":{"accession":"P49069","domains":[{"cath_id":"-","chopping":"184-295","consensus_level":"high","plddt":75.449,"start":184,"end":295}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49069","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49069-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49069-F1-predicted_aligned_error_v6.png","plddt_mean":61.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAMLG","jax_strain_url":"https://www.jax.org/strain/search?query=CAMLG"},"sequence":{"accession":"P49069","fasta_url":"https://rest.uniprot.org/uniprotkb/P49069.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49069/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49069"}},"corpus_meta":[{"pmid":"9311921","id":"PMC_9311921","title":"NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9311921","citation_count":294,"is_preprint":false},{"pmid":"12919676","id":"PMC_12919676","title":"CAML is required for efficient EGF receptor recycling.","date":"2003","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/12919676","citation_count":61,"is_preprint":false},{"pmid":"24392163","id":"PMC_24392163","title":"WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24392163","citation_count":55,"is_preprint":false},{"pmid":"15668245","id":"PMC_15668245","title":"Identification of calcium-modulating cyclophilin ligand (CAML) as transducer of angiotensin II-mediated nuclear factor of activated T cells (NFAT) activation.","date":"2005","source":"The Journal of biological 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development.","date":"2005","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/16111633","citation_count":30,"is_preprint":false},{"pmid":"26100089","id":"PMC_26100089","title":"TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development.","date":"2015","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26100089","citation_count":30,"is_preprint":false},{"pmid":"21514638","id":"PMC_21514638","title":"Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B-cell dysfunction in patients with Smith-Magenis syndrome.","date":"2011","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21514638","citation_count":23,"is_preprint":false},{"pmid":"19229138","id":"PMC_19229138","title":"CAML loss causes anaphase failure and chromosome missegregation.","date":"2009","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/19229138","citation_count":19,"is_preprint":false},{"pmid":"20582322","id":"PMC_20582322","title":"Transmembrane and ubiquitin-like domain containing 1 (Tmub1) regulates locomotor activity and wakefulness in mice and interacts with CAMLG.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20582322","citation_count":17,"is_preprint":false},{"pmid":"31417168","id":"PMC_31417168","title":"The WRB Subunit of the Get3 Receptor is Required for the Correct Integration of its Partner CAML into the ER.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31417168","citation_count":17,"is_preprint":false},{"pmid":"30154321","id":"PMC_30154321","title":"Classical Swine Fever Virus p7 Protein Interacts with Host Protein CAMLG and Regulates Calcium Permeability at the Endoplasmic Reticulum.","date":"2018","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/30154321","citation_count":14,"is_preprint":false},{"pmid":"32340409","id":"PMC_32340409","title":"Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32340409","citation_count":13,"is_preprint":false},{"pmid":"35262690","id":"PMC_35262690","title":"CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35262690","citation_count":12,"is_preprint":false},{"pmid":"21128111","id":"PMC_21128111","title":"CAML promotes prolactin-dependent proliferation of breast cancer cells by facilitating prolactin receptor signaling pathways.","date":"2010","source":"Breast cancer research and 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eukaryotes.","date":"2020","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/32715580","citation_count":6,"is_preprint":false},{"pmid":"40518771","id":"PMC_40518771","title":"CAML: Commutative Algebra Machine Learning─A Case Study on Protein-Ligand Binding Affinity Prediction.","date":"2025","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/40518771","citation_count":6,"is_preprint":false},{"pmid":"38294253","id":"PMC_38294253","title":"Identification of Intestinal Lamina Propria Plasma Cells by Surface Transmembrane Activator and CAML Interactor Expression.","date":"2024","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/38294253","citation_count":4,"is_preprint":false},{"pmid":"20126395","id":"PMC_20126395","title":"CAML does not modulate tetherin-mediated restriction of HIV-1 particle release.","date":"2010","source":"PloS 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39467771","citation_count":1,"is_preprint":false},{"pmid":"39823474","id":"PMC_39823474","title":"Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39823474","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14151,"output_tokens":4887,"usd":0.057879,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13130,"output_tokens":4600,"usd":0.090325,"stage2_stop_reason":"end_turn"},"total_usd":0.148204,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"CAML acts as a signaling intermediate downstream of TACI (a TNF receptor superfamily member). Cross-linking of TACI activated NF-AT, AP-1, and NF-κB transcription factors, and a dominant-negative CAML mutant specifically blocked TACI-induced NF-AT activation, placing CAML in the TACI signaling pathway.\",\n      \"method\": \"Dominant-negative mutant transfection, transcriptional reporter assays, antibody cross-linking in Jurkat T cells\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative functional assay with reporter readout, single lab, two orthogonal approaches (overexpression + dominant-negative block)\",\n      \"pmids\": [\"9311921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CAML is required for recycling of internalized EGF receptor (EGFR) back to the plasma membrane. CAML-deficient cells show normal EGFR internalization and EGF-induced signaling but defective receptor recycling and reduced surface EGFR accumulation. CAML directly associates with the kinase domain of EGFR in a ligand-dependent manner.\",\n      \"method\": \"CAML gene knockout (mouse embryonic fibroblasts), EGF receptor trafficking assays (surface accumulation, internalization, recycling), co-immunoprecipitation\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype plus direct binding assay, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"12919676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CAML interacts with ATRAP (AT1 receptor-associated protein) via its N-terminal hydrophilic domain (aa 1–189) and functions as a signal transducer for angiotensin II-mediated NFAT activation. ATRAP overexpression decreased CAML/Ang II-induced NFAT activation, while ATRAP knockdown increased NFAT activity; the CAML N-terminal domain (aa 1–189) sensitized NFAT activation in response to Ang II. The CAML–ATRAP interaction localizes to ER vesicular structures.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), immunofluorescence colocalization, RNA interference, transcriptional reporter assays in HEK293 cells\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (yeast 2-hybrid, co-IP, BRET, reporter assays, RNAi) in single lab study\",\n      \"pmids\": [\"15668245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CAML interacts with p56Lck and regulates its subcellular localization in resting and TCR-stimulated thymocytes. CAML-deficient thymocytes show enhanced p56Lck and ZAP-70 phosphorylation and increased IL-2 production and cell death after TCR stimulation, indicating CAML acts as a negative regulator of p56Lck signaling. CAML is essential for positive selection and suppression of negative selection during thymopoiesis.\",\n      \"method\": \"Conditional CAML knockout in mouse thymocytes, co-immunoprecipitation, kinase phosphorylation assays, IL-2 production assays, flow cytometry of thymocyte populations\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined developmental phenotype plus direct binding and signaling assays, multiple orthogonal methods\",\n      \"pmids\": [\"16111633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The intracellular C-terminus of fibrocystin (ARPKD protein) directly interacts with CAML. Both proteins co-localize in the apical membrane, primary cilia, and basal body of distal nephron cells.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from COS7 cells, immunofluorescence colocalization\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single co-IP confirmation of yeast 2-hybrid hit without functional follow-up on CAML mechanism\",\n      \"pmids\": [\"16243292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CAML loss causes anaphase failure and chromosome missegregation. CAML-deficient MEFs fail to segregate chromosomes in anaphase (a 'cut' phenotype), have spindle dysfunction, lagging/misaligned chromosomes and chromatin bridges, a modestly weakened spindle assembly checkpoint (SAC), and increased aneuploidy. CAML functions as a regulator of mitotic spindle function and a modulator of SAC maintenance.\",\n      \"method\": \"Cre-loxP conditional knockout MEFs, live-cell imaging, spindle assembly checkpoint assays, aneuploidy measurement by cytogenetics\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined mitotic phenotype across multiple readouts (imaging, SAC assay, aneuploidy) in single study\",\n      \"pmids\": [\"19229138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CAML-deficient thymocytes accumulate high levels of reactive oxygen species (ROS) and undergo accelerated apoptosis. Genetic removal of the pro-apoptotic BH3-only protein Bim (but not deletion of p53 or Fas) significantly rescued survival of CAML-deficient thymocytes, placing CAML upstream of Bim-dependent apoptosis in thymocyte survival.\",\n      \"method\": \"Conditional knockout, genetic epistasis (CAML KO × Bim KO double mutant mice), ROS measurement, in vitro apoptosis assays\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double-mutant rescue provides clear pathway placement, multiple death stimuli tested\",\n      \"pmids\": [\"20300112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CAML interacts with TMUB1 (C7orf21/HOPS). The interaction was identified by yeast two-hybrid screen of a brain library and confirmed by co-immunoprecipitation in HEK cells. Both proteins co-localize in the cytoplasm.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in HEK cells, immunofluorescence colocalization\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single co-IP confirmation without further mechanistic dissection of CAML function\",\n      \"pmids\": [\"20582322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CAML does not contribute to tetherin-mediated restriction of HIV-1 particle release. Stable depletion of CAML in HeLa cells had no effect on cell-surface tetherin levels and did not relieve tetherin-mediated restriction.\",\n      \"method\": \"Stable shRNA knockdown of CAML, flow cytometry for tetherin surface levels, HIV particle release assays\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean stable knockdown with multiple functional readouts; negative result robustly established\",\n      \"pmids\": [\"20126395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CAML is required for prolactin receptor (PRLR) signaling. CAML associates with PRLR and this interaction is augmented by PRL stimulation. CAML silencing impairs PRLR-dependent Stat5 and Mek1/2 activation, PRL internalization with cyclophilin B, PRLR recycling, and Ca2+ mobilization, thereby reducing PRL-dependent proliferation of breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing, signaling pathway assays (Stat5, Mek1/2 phosphorylation), Ca2+ measurement, receptor recycling assays\",\n      \"journal\": \"Breast Cancer Research and Treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP binding plus RNAi loss-of-function with multiple signaling readouts, single lab\",\n      \"pmids\": [\"21128111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CAML is essential for survival of peripheral follicular (Fo) B cells. Conditional deletion of CAML in B cells caused reduced Fo B cell numbers, increased cellular turnover, and increased apoptosis after LPS and IL-4 stimulation, establishing an ongoing anti-apoptotic role for CAML in mature B cells.\",\n      \"method\": \"Conditional B cell-specific CAML knockout (CD19-Cre), flow cytometry, in vitro apoptosis assays, inducible gene deletion in mature B cells\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional and inducible knockout with multiple functional readouts confirming cell-autonomous survival role\",\n      \"pmids\": [\"22351938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"WRB and CAML together form a functional receptor complex for TRC40 (Get3) at the ER membrane and are both necessary and sufficient for tail-anchored (TA) protein targeting and insertion into the ER. The transmembrane segments of CAML are essential for creating a functional receptor with WRB. Binding parameters of TRC40 to the WRB/CAML receptor were determined. Yeast lacking GET1 and GET2 are functionally complemented by WRB and CAML.\",\n      \"method\": \"Yeast complementation assay (GET1/GET2 deletion complementation), in vivo TA protein targeting assays, binding affinity measurement (TRC40 to WRB/CAML), domain mutagenesis of CAML transmembrane segments\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic complementation, direct binding quantification, and domain mutagenesis establishing sufficiency and structure-function in one study\",\n      \"pmids\": [\"24392163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CAML supports survival and mitotic progression in Myc-driven B-cell lymphomas independently of its TA protein insertion function. The C-terminal 111 amino acid region of CAML (encompassing the WRB-binding domain but not the TRC40-interaction domain) was sufficient to rescue survival and growth of CAML-deleted lymphoma cells without restoring TA protein insertion. Cell death was blocked by Bcl-2/Bcl-xL overexpression. Loss of CAML caused G2/M arrest with low phospho-histone H3.\",\n      \"method\": \"Tamoxifen-inducible conditional knockout in Eμ-Myc lymphoma cells, domain deletion/rescue experiments, cell cycle analysis, Bcl-2/Bcl-xL overexpression rescue, in vivo tumor regression assay\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with domain-swap rescue experiments dissecting TA insertion vs. survival function, multiple orthogonal readouts\",\n      \"pmids\": [\"28580168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAML interacts with TMUB1 via TMUB1's TM1 hydrophobic domain. TMUB1 overexpression abolishes the interaction between CAML and its downstream binding partner cyclophilin B, thereby reducing intracellular Ca2+ ([Ca2+]i) and inhibiting hepatocyte proliferation. CAML–cyclophilin B interaction acts upstream of calcineurin to regulate Ca2+ signaling during proliferation.\",\n      \"method\": \"Co-immunoprecipitation in BRL-3A rat hepatocytes, Ca2+ influx measurement, TMUB1 overexpression and knockout, TM1 domain deletion mutant\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain deletion plus functional readouts (Ca2+ and proliferation), single lab\",\n      \"pmids\": [\"29967478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Classical Swine Fever Virus p7 interacts with CAMLG at the ER membrane, and this interaction is required for p7-mediated calcium permeability at the ER. Mutant p7 forms unable to interact with CAMLG failed to mediate calcium permeability and showed decreased virulence.\",\n      \"method\": \"Yeast two-hybrid, confocal colocalization in eukaryotic cells with p7 mutants, calcium permeability assays in ER\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast 2-hybrid confirmed by colocalization with mutagenesis plus functional Ca2+ permeability assay, single lab\",\n      \"pmids\": [\"30154321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WRB is required for the correct topological integration of CAML into the ER membrane. Without sufficient WRB, CAML fails to adopt its correct three-transmembrane-segment topology and instead generates two aberrant topoforms that congregate in ER-associated clusters and are degraded by the proteasome. WRB acts catalytically to assist CAML topogenesis, consistent with WRB being a member of the Oxa1 superfamily.\",\n      \"method\": \"Topology mapping (CAML topology determination), WRB knockdown/depletion, proteasome inhibitor treatment, immunofluorescence of aberrant CAML clusters, cell fractionation\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct topology determination combined with WRB depletion and proteasome inhibition, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31417168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of functional CAML (via homozygous splice variant c.633+4A>G) causes mislocalization of syntaxin-5 and drastic reduction of Bet1L (v-SNARE) in patient fibroblasts and siCAMLG-depleted HeLa cells, indicating CAML (as part of the TRC pathway) is required for proper assembly of Golgi SNARE complexes and correct TA protein insertion. This CAML deficiency causes a congenital disorder of glycosylation (combined O-linked and type II N-linked glycosylation defect).\",\n      \"method\": \"Patient fibroblast analysis (homozygous splice variant), siRNA knockdown in HeLa cells, Western blot and immunofluorescence of syntaxin-5 and Bet1L, glycosylation biochemical analysis\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human patient genetics confirmed in two independent cellular models (patient fibroblasts + siRNA HeLa), multiple mechanistic readouts\",\n      \"pmids\": [\"35262690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAML is required for motor neuron survival and neuromuscular function via its role in the TRC pathway for TA protein insertion. Neuron-specific CAML deletion causes hind limb weakness, paralysis, and loss of spinal motor neuron cell bodies. CAML depletion perturbs intracellular trafficking: aberrant procathepsin D release, defective CD222 retention in the trans-Golgi network, reduced and mislocalized syntaxin-5, dysfunctional lysosomes, and abnormal protein glycosylation. Neuronal deletion of ASNA1 (TRC40/GET3) produces an identical phenotype, confirming the mechanistic link to the TRC pathway.\",\n      \"method\": \"Neuron-specific conditional knockout (SLICK-H-Cre and synapsin-Cre), global hypomorphic CAML mice, histology of spinal cord, intracellular trafficking assays (procathepsin D secretion, CD222 localization, syntaxin-5 localization), glycosylation analysis, ASNA1 neuronal KO genetic epistasis\",\n      \"journal\": \"PLoS Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent Cre lines, genetic epistasis with ASNA1 KO, and multiple mechanistic trafficking readouts in single rigorous study\",\n      \"pmids\": [\"39823474\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAML (CAMLG) is an ER transmembrane protein that functions as part of the WRB/CAML heteromeric receptor complex to capture TRC40 (ASNA1/GET3) and mediate post-translational insertion of tail-anchored (TA) proteins into the ER membrane; WRB catalytically assists CAML's own three-TM topogenesis, and together they govern Golgi SNARE assembly, intracellular trafficking, and protein glycosylation. In addition to this core TA-insertion role, CAML acts as a signaling scaffold that interacts with p56Lck to negatively regulate TCR signaling and thymocyte selection, promotes EGF and prolactin receptor recycling, transduces TACI- and angiotensin II-induced NF-AT/AP-1/NF-κB activation, regulates mitotic spindle function and the spindle assembly checkpoint, and suppresses Bim-dependent thymocyte apoptosis—with a separable C-terminal domain supporting lymphoma cell survival and mitotic progression independently of TA protein insertion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAMLG (CAML) is an ER transmembrane protein that, together with WRB, forms the membrane receptor for TRC40/ASNA1 (GET3) and mediates post-translational insertion of tail-anchored proteins into the ER, with CAML's transmembrane segments being essential for a functional receptor that is both necessary and sufficient to support TA targeting and to complement yeast lacking GET1/GET2 [#11]. CAML's own three-transmembrane topology depends catalytically on WRB; without sufficient WRB, CAML mis-integrates into aberrant topoforms that cluster in the ER and are degraded by the proteasome [#15]. Through this TRC pathway, CAML governs assembly of Golgi SNAREs—loss of CAML mislocalizes syntaxin-5 and depletes the v-SNARE Bet1L—and is required for correct protein glycosylation and intracellular trafficking, including procathepsin D handling and CD222 retention in the trans-Golgi network [#16, #17]. Biallelic loss-of-function of CAMLG causes a congenital disorder of glycosylation with combined O-linked and type II N-linked defects [#16], and neuron-specific CAML deletion produces motor neuron loss and paralysis phenocopied by neuronal ASNA1 deletion, confirming the shared TRC mechanism [#17]. Beyond TA insertion, CAML acts as a signaling and survival scaffold: it associates ligand-dependently with EGFR and the prolactin receptor to promote their recycling and downstream signaling [#1, #9], binds p56Lck to negatively regulate TCR signaling and control thymocyte selection [#3], and is required for thymocyte and follicular B-cell survival by acting upstream of Bim-dependent apoptosis [#6, #10]. CAML also regulates mitotic spindle function and anaphase chromosome segregation [#5], and a separable C-terminal region supports survival and mitotic progression of Myc-driven lymphoma cells independently of TA protein insertion [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established CAML as a signaling intermediate by placing it in the TACI pathway, the first functional assignment for the protein.\",\n      \"evidence\": \"Dominant-negative mutant and transcriptional reporter assays in Jurkat T cells\",\n      \"pmids\": [\"9311921\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism of how CAML links TACI to NF-AT not resolved\", \"Direct biochemical contact with TACI not demonstrated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed CAML controls receptor trafficking rather than internalization, defining a recycling role through direct, ligand-dependent association with the EGFR kinase domain.\",\n      \"evidence\": \"CAML gene knockout MEFs with EGFR trafficking assays and co-immunoprecipitation\",\n      \"pmids\": [\"12919676\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of CAML-EGFR binding unknown\", \"How CAML mechanistically routes receptors to recycling not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Extended CAML's signaling-scaffold role to angiotensin II via an ATRAP interaction at the ER and to TCR signaling via p56Lck, and tied it to thymocyte selection.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, BRET, reporter assays in HEK293; conditional thymocyte knockout with kinase and flow-cytometry readouts; yeast two-hybrid/co-IP for fibrocystin\",\n      \"pmids\": [\"15668245\", \"16111633\", \"16243292\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"The fibrocystin/ciliary interaction (idx 4) is a single co-IP without functional follow-up\", \"How a single ER protein integrates multiple receptor signals mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed an unexpected mitotic function, showing CAML loss causes anaphase failure, spindle dysfunction and aneuploidy with a weakened spindle assembly checkpoint.\",\n      \"evidence\": \"Cre-loxP conditional knockout MEFs with live-cell imaging, SAC assays, and cytogenetics\",\n      \"pmids\": [\"19229138\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular target of CAML at the spindle/SAC not identified\", \"Connection between ER role and mitotic role unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed CAML upstream of Bim-dependent apoptosis as a survival factor in thymocytes and ruled out a role in tetherin-mediated HIV restriction, while adding prolactin receptor signaling/recycling to its trafficking repertoire.\",\n      \"evidence\": \"CAML×Bim double-knockout epistasis with ROS/apoptosis assays; stable shRNA knockdown with HIV release assays; co-IP and siRNA with PRLR signaling and recycling readouts; yeast two-hybrid/co-IP for TMUB1\",\n      \"pmids\": [\"20300112\", \"20126395\", \"21128111\", \"20582322\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How CAML restrains Bim/ROS mechanistically not defined\", \"TMUB1 interaction (idx 7) functionally uncharacterized at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated an ongoing, cell-autonomous anti-apoptotic requirement for CAML in mature follicular B cells, generalizing its survival function beyond development.\",\n      \"evidence\": \"B cell-specific and inducible conditional knockout with flow cytometry and apoptosis assays\",\n      \"pmids\": [\"22351938\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Survival pathway in B cells not molecularly mapped\", \"Whether the same Bim axis operates in B cells untested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined CAML's core molecular identity, showing WRB/CAML together are necessary and sufficient as the TRC40 receptor for tail-anchored protein insertion at the ER.\",\n      \"evidence\": \"Yeast GET1/GET2 complementation, in vivo TA targeting, TRC40 binding affinity measurement, and CAML transmembrane mutagenesis\",\n      \"pmids\": [\"24392163\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structure of the WRB/CAML/TRC40 complex not determined\", \"Coupling between TA insertion and CAML's signaling roles unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Separated CAML's survival/mitotic activity from its insertase function, showing a C-terminal WRB-binding region rescues lymphoma cell survival without restoring TA insertion.\",\n      \"evidence\": \"Inducible knockout in Eμ-Myc lymphoma with domain-deletion rescue, cell cycle analysis, Bcl-2/Bcl-xL rescue, and in vivo tumor regression\",\n      \"pmids\": [\"28580168\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"The effector engaged by the C-terminal domain to promote survival not identified\", \"How the same domain drives G2/M progression mechanistically unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked CAML to calcium signaling, showing TMUB1 displaces CAML from cyclophilin B to lower intracellular Ca2+, and identified a viral subversion of CAML-dependent ER calcium permeability.\",\n      \"evidence\": \"Co-IP with domain deletions and Ca2+/proliferation readouts in hepatocytes; yeast two-hybrid, colocalization, and Ca2+ permeability assays with viral p7 mutants\",\n      \"pmids\": [\"29967478\", \"30154321\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct CAML-cyclophilin B-calcineurin biochemistry not fully reconstituted\", \"Physiological breadth of CAML calcium control across cell types untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Clarified the biogenesis hierarchy, showing WRB catalytically assists CAML's own three-TM topogenesis and that mis-topologized CAML is proteasomally degraded.\",\n      \"evidence\": \"CAML topology mapping with WRB depletion, proteasome inhibition, immunofluorescence of aberrant clusters, and fractionation\",\n      \"pmids\": [\"31417168\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Catalytic mechanism by which WRB drives CAML integration not detailed\", \"Quality-control machinery degrading mis-topologized CAML not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected CAML to human disease, establishing that biallelic CAMLG loss disrupts Golgi SNARE assembly (syntaxin-5, Bet1L) and causes a congenital disorder of glycosylation.\",\n      \"evidence\": \"Patient fibroblasts with a homozygous splice variant plus siRNA HeLa models, SNARE Western/immunofluorescence, and glycosylation analysis\",\n      \"pmids\": [\"35262690\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Full spectrum of TA substrates whose mislocalization drives the CDG phenotype not enumerated\", \"Genotype-phenotype relationship across additional patients not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated an in vivo TRC-pathway requirement for CAML in motor neuron survival, with ASNA1 deletion phenocopying CAML loss to confirm the mechanism and tie it to trafficking and glycosylation defects.\",\n      \"evidence\": \"Multiple neuron-specific Cre lines and hypomorphic mice, spinal cord histology, procathepsin D/CD222/syntaxin-5 trafficking assays, glycosylation analysis, and ASNA1 neuronal-KO epistasis\",\n      \"pmids\": [\"39823474\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity of the critical neuronal TA substrate(s) underlying motor neuron loss not pinpointed\", \"Why neurons are particularly vulnerable to TRC-pathway loss not explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CAML's single core insertase activity mechanistically gives rise to its diverse receptor-recycling, calcium-signaling, anti-apoptotic, and mitotic functions, and whether these reflect distinct TA substrates or insertion-independent activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No unifying substrate map linking TA insertion to the signaling/survival phenotypes\", \"No high-resolution structure of the WRB/CAML/TRC40 receptor\", \"Effector mediating the insertion-independent C-terminal survival function unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [11, 16, 17]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 3, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 11, 14, 15]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 16, 17]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 9, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 10, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"complexes\": [\"WRB/CAML TRC40 receptor\"],\n    \"partners\": [\"WRB\", \"ASNA1\", \"EGFR\", \"PRLR\", \"LCK\", \"ATRAP\", \"TMUB1\", \"PPIB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}