{"gene":"WHAMM","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2012,"finding":"WHAMM binds to the outer surface of microtubule protofilaments via a novel interaction between its central coiled-coil region and tubulin heterodimers; upon MT binding, the N-terminal membrane-binding domain is exposed at the MT periphery to recruit and remodel vesicles into tubular structures, while MT binding simultaneously masks the C-terminal WCA domain and prevents actin nucleation activity.","method":"Cryo-electron microscopy, biophysical and biochemical approaches (in vitro binding assays, domain mutagenesis)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with biochemical/biophysical validation, multiple orthogonal methods in one study","pmids":["23027905"],"is_preprint":false},{"year":2017,"finding":"WHAMM interacts with αβ-tubulin through a small peptide motif (MT-binding motif, MBM) within its MT-binding domain; cryo-EM reconstruction revealed the atomic-level arrangement of MBM around MTs, and chemical cross-linking/mass spectrometry confirmed a conformational switch of the MBM between the non-MT-bound and MT-bound states.","method":"Cryo-electron microscopy, chemical cross-linking, mass spectrometry","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with orthogonal biochemical validation (cross-linking MS), single lab but multiple rigorous methods","pmids":["28351611"],"is_preprint":false},{"year":2016,"finding":"Active Rab1 (GTP-bound) recruits WHAMM to dynamic tubulovesicular structures and a prenylated active form of Rab1 binds directly to an N-terminal domain of WHAMM in vitro; paradoxically, Rab1 binding inhibits WHAMM-mediated Arp2/3-dependent actin assembly, representing a strategy where a Rab G-protein recruits the nucleation machinery but dampens its activity.","method":"Co-localization in fibroblasts, in vitro direct binding assay (prenylated Rab1 pulldown with N-terminal WHAMM domain), actin assembly assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro binding assay plus cell-based functional readout (tubule formation, actin assembly), two orthogonal methods in one study","pmids":["26823012"],"is_preprint":false},{"year":2015,"finding":"WHAMM directs Arp2/3 complex activity at the ER to drive autophagosome biogenesis via an actin comet-tail mechanism; WHAMM puncta colocalize and comigrate with autophagy markers LC3, DFCP1, and p62, and knockdown of WHAMM or mutagenesis blocking its interaction with Arp2/3 complex reduces autophagosome size and number.","method":"Live-cell imaging, siRNA knockdown, Arp2/3-interaction mutagenesis, pharmacological inhibition of actin polymerization and Arp2/3 complex","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (KD, mutagenesis, pharmacology, live imaging) replicated across two companion papers (PMID 26096974, 26291929)","pmids":["26096974","26291929"],"is_preprint":false},{"year":2019,"finding":"WHAMM is required for autophagic lysosome reformation (ALR): it is recruited to the autolysosome membrane through specific binding to PI(4,5)P2, then promotes assembly of an actin scaffold on the autolysosome surface to drive tubulation. WHAMM knockout causes accumulation of enlarged autolysosomes during prolonged starvation.","method":"WHAMM knockout, lipid-binding assay (PI(4,5)P2 interaction), live-cell imaging of autolysosome tubulation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO with specific cellular phenotype, direct lipid-binding assay, and live imaging, multiple orthogonal methods in one study","pmids":["31420534"],"is_preprint":false},{"year":2017,"finding":"WHAMM binds to PI(3)P and promotes actin nucleation at nascent autophagosomes; patient cells harboring a WHAMM founder mutation show cytoskeletal irregularities and severe autophagy defects, and reintroduction of wild-type WHAMM restores autophagosomal biogenesis; WHAMM inactivation in healthy cells inhibits LC3 lipidation and clearance of ubiquitinated aggregates.","method":"Patient cell complementation, WHAMM inactivation (siRNA/mutation), PI(3)P binding assay, LC3 lipidation assay, ubiquitinated aggregate clearance assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — complementation in patient cells plus multiple biochemical readouts, single lab but orthogonal methods","pmids":["28720660"],"is_preprint":false},{"year":2024,"finding":"WHAMM and its binding partner the Arp2/3 complex control autophagosomal membrane closure and cargo receptor recruitment in mouse fibroblasts and human proximal tubule cells; loss of WHAMM causes accumulation of lipidated LC3 in kidney tissue and structural abnormalities of the proximal tubule affecting nutrient reabsorption in male knockout mice.","method":"WHAMM knockout mice (physiological phenotype), autophagy flux assays (LC3 lipidation), membrane closure assays in cell lines","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with defined phenotype plus cell-based mechanistic assays, peer-reviewed publication","pmids":["38598293"],"is_preprint":false},{"year":2021,"finding":"WHAMM promotes the intrinsic (mitochondrial) apoptosis pathway in a p53-dependent manner, enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation; actin filaments assembled via Arp2/3 complex appear in cytoplasmic territories containing cytochrome c clusters and active caspase-3; RhoD (a WHAMM-interacting G-protein) opposes this cell death pathway.","method":"WASP-family gene inactivation (CRISPR/siRNA), caspase cleavage assays, cytochrome c release assay, live-cell imaging, RhoD depletion/deletion epistasis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple biochemical readouts and epistasis (RhoD), single lab","pmids":["33872315"],"is_preprint":false},{"year":2025,"finding":"WHAMM controls actin-mediated cytochrome c release from mitochondria and ASC speck formation in kidney tubule cells, connecting WHAMM-driven actin dynamics to cell death pathways; pharmacological inhibition of actin dynamics mitigates kidney disease in cisplatin, folic acid, and UUO experimental models.","method":"Genetic deletion of Whamm in mice (disease models), in vitro cell studies (cytochrome c release, ASC speck assay), pharmacological actin inhibition","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse disease models plus cell-based mechanistic assays, single lab, multiple readouts","pmids":["40138314"],"is_preprint":false},{"year":2012,"finding":"WHAMM localizes to the meiotic spindle in mouse oocytes (after meiosis resumption, not at GV stage), and depletion by siRNA causes failure of spindle migration, disruption of actin cap formation, asymmetric cytokinesis failure, and decreased first polar body extrusion.","method":"Immunostaining, siRNA microinjection in mouse oocytes, nocodazole/taxol treatment","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, siRNA knockdown with cellular phenotype but limited mechanistic resolution of pathway","pmids":["23160625"],"is_preprint":false},{"year":2021,"finding":"WHAMM co-localizes with the actin cage permeating the meiotic spindle in mouse oocytes; depletion impairs spindle formation, displaces the MTOC, disrupts spindle actin formation, and causes chromosomal aneuploidy and abnormal asymmetric division; BFA treatment disperses WHAMM localization, linking ER-to-Golgi trafficking to WHAMM's spindle function.","method":"siRNA knockdown in mouse oocytes, immunofluorescence, brefeldin A (BFA) treatment","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, KD with cellular phenotypes but no direct pathway reconstitution","pmids":["33397186"],"is_preprint":false},{"year":2020,"finding":"WHAMM's interaction with actin is required for initiation of autophagy; in SETD2-null cells the WHAMM–actin interaction is reduced, leading to autophagy defects; this deficit is rescued by pharmacological induction of actin polymerization (jasplakinolide), indicating that the impaired interaction results from altered actin dynamics rather than direct loss of the SETD2-mediated ActK68me3 mark.","method":"Co-immunoprecipitation (WHAMM–actin), SETD2 knockout cells, jasplakinolide rescue, autophagy flux assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with partial mechanistic follow-up, single lab, single publication","pmids":["33036756"],"is_preprint":false},{"year":2024,"finding":"WHAMM enhances autophagosomal localization of TGF-β1 and promotes autophagic degradation of TGF-β1 in type II alveolar epithelial cells, thereby suppressing TGF-β1-driven EMT; knockdown of WHAMM causes accumulation of TGF-β1 and increased EMT markers in a hyperoxia-induced BPD model.","method":"WHAMM knockdown/overexpression, autophagy flux assays, TGF-β1 colocalization with autophagosome markers, EMT marker analysis","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD/OE with cellular readouts but limited mechanistic resolution of how WHAMM targets TGF-β1 to autophagosomes","pmids":["39564703"],"is_preprint":false}],"current_model":"WHAMM is a Wiskott-Aldrich Syndrome protein family nucleation-promoting factor (NPF) that activates the Arp2/3 complex to polymerize branched actin filaments; it binds microtubules via a short peptide motif in its coiled-coil domain (which simultaneously suppresses its actin nucleation activity), recruits membranes through its N-terminal domain (engaging PI(3)P and PI(4,5)P2 on distinct organelles), and functions at the ER/autophagosome interface to drive autophagosome biogenesis, membrane closure, and autophagic lysosome reformation via actin comet-tail formation; it is regulated upstream by Rab1, which recruits WHAMM to tubulovesicular structures but inhibits its nucleation activity, and it additionally participates in intrinsic apoptosis by promoting mitochondrial permeabilization and caspase activation in an Arp2/3-dependent manner."},"narrative":{"mechanistic_narrative":"WHAMM is a Wiskott-Aldrich Syndrome protein family nucleation-promoting factor that activates the Arp2/3 complex to drive branched actin polymerization in service of membrane remodeling, autophagy, and intrinsic apoptosis [PMID:26096974, PMID:26291929, PMID:28720660]. Its central coiled-coil region binds the outer surface of microtubule protofilaments through a short MT-binding peptide motif that adopts distinct conformations in the free and MT-bound states; this engagement exposes the N-terminal membrane-binding domain to recruit and tubulate vesicles while simultaneously masking the C-terminal WCA domain to suppress actin nucleation [PMID:23027905, PMID:28351611]. WHAMM is recruited to membranes through phosphoinositide engagement—PI(3)P at nascent autophagosomes and PI(4,5)P2 at autolysosomes—and through the GTP-bound G-protein Rab1, which paradoxically recruits the nucleation machinery to tubulovesicular structures while dampening its Arp2/3-dependent actin assembly [PMID:26823012, PMID:31420534, PMID:28720660]. Functionally, WHAMM directs Arp2/3 activity at the ER to nucleate actin comet tails that build autophagosomes, controls autophagosomal membrane closure and cargo receptor recruitment, and drives actin-scaffold-dependent tubulation required for autophagic lysosome reformation; its loss impairs LC3 lipidation, autophagic flux, and clearance of ubiquitinated aggregates [PMID:26096974, PMID:26291929, PMID:31420534, PMID:28720660, PMID:38598293]. Independently, WHAMM promotes the intrinsic mitochondrial apoptosis pathway in an Arp2/3- and p53-dependent manner, enhancing mitochondrial permeabilization, cytochrome c release, and caspase activation, with RhoD opposing this death pathway [PMID:33872315, PMID:40138314]. A WHAMM founder mutation in patient cells produces cytoskeletal irregularities and severe autophagy defects rescued by wild-type WHAMM, and Whamm-knockout mice show LC3 accumulation and proximal tubule structural abnormalities [PMID:28720660, PMID:38598293].","teleology":[{"year":2012,"claim":"Resolving how WHAMM couples microtubules to membrane remodeling established that its coiled-coil binds tubulin while its termini are conformationally gated—MT binding exposes the membrane-binding domain and silences actin nucleation.","evidence":"Cryo-EM of WHAMM on microtubules with in vitro binding assays and domain mutagenesis","pmids":["23027905"],"confidence":"High","gaps":["Did not define the in vivo trigger that releases the WCA domain for nucleation","Physiological setting of MT-templated vesicle tubulation not established"]},{"year":2012,"claim":"Identifying WHAMM at the meiotic spindle extended its role beyond interphase trafficking to actin- and microtubule-dependent asymmetric division.","evidence":"Immunostaining and siRNA microinjection in mouse oocytes with nocodazole/taxol treatment","pmids":["23160625"],"confidence":"Medium","gaps":["No molecular mechanism linking WHAMM to spindle migration","Whether Arp2/3 activation underlies the actin cap defect not tested"]},{"year":2015,"claim":"Connecting WHAMM to autophagosome biogenesis showed it directs Arp2/3-mediated actin comet tails at the ER, defining a cytoskeletal driver of early autophagy.","evidence":"Live-cell imaging, siRNA knockdown, Arp2/3-interaction mutagenesis, and pharmacological actin/Arp2/3 inhibition across two companion papers","pmids":["26096974","26291929"],"confidence":"High","gaps":["How WHAMM is initially targeted to the ER/autophagosome interface not resolved here","Relationship between comet-tail force and membrane shaping not quantified"]},{"year":2016,"claim":"Defining Rab1 as an upstream recruiter clarified that a Rab GTPase positions WHAMM on tubulovesicular structures yet restrains its actin-nucleating output.","evidence":"Co-localization in fibroblasts, in vitro prenylated-Rab1 binding to N-terminal WHAMM, and actin assembly assays","pmids":["26823012"],"confidence":"High","gaps":["Signal relieving Rab1-mediated inhibition unknown","Whether Rab1 regulation operates during autophagy specifically not tested"]},{"year":2017,"claim":"Mapping phosphoinositide and tubulin binding plus patient-cell complementation established WHAMM's PI(3)P-dependent membrane recruitment and causal role in human autophagy.","evidence":"Cryo-EM of the MT-binding motif with cross-linking MS; patient cell complementation, PI(3)P binding, LC3 lipidation and aggregate-clearance assays","pmids":["28351611","28720660"],"confidence":"High","gaps":["Identity of the disease and full genotype-phenotype relationship not detailed in the corpus","How PI(3)P binding is coordinated with Arp2/3 activation unresolved"]},{"year":2019,"claim":"Demonstrating WHAMM in autophagic lysosome reformation showed its membrane targeting is lipid-context-specific—PI(4,5)P2 at autolysosomes—driving actin-scaffold tubulation distinct from biogenesis.","evidence":"WHAMM knockout, PI(4,5)P2 lipid-binding assay, and live imaging of autolysosome tubulation","pmids":["31420534"],"confidence":"High","gaps":["How WHAMM switches between PI(3)P and PI(4,5)P2 membranes not defined","Force-generation mechanism for tubulation not reconstituted"]},{"year":2021,"claim":"Linking WHAMM to intrinsic apoptosis revealed an Arp2/3- and p53-dependent role in mitochondrial permeabilization and caspase activation, with RhoD as an opposing regulator.","evidence":"WASP-family gene inactivation (CRISPR/siRNA), caspase and cytochrome c release assays, live imaging, and RhoD epistasis","pmids":["33872315"],"confidence":"Medium","gaps":["How actin filaments mechanistically promote mitochondrial permeabilization unclear","RhoD-WHAMM physical interaction in death context not structurally defined"]},{"year":2024,"claim":"In vivo knockout established WHAMM's requirement for autophagosomal membrane closure and cargo receptor recruitment, with physiological consequences in kidney proximal tubule function.","evidence":"Whamm knockout mice with LC3 lipidation flux assays and membrane closure assays in cell lines","pmids":["38598293"],"confidence":"High","gaps":["Molecular mechanism of closure versus cargo recruitment not separated","Tissue specificity of the phenotype not fully explained"]},{"year":2025,"claim":"Extending WHAMM's death-promoting role to disease, actin-mediated cytochrome c release and ASC speck formation were connected to experimental kidney injury treatable by actin inhibition.","evidence":"Whamm-deletion mouse disease models (cisplatin, folic acid, UUO), cytochrome c and ASC speck assays, pharmacological actin inhibition","pmids":["40138314"],"confidence":"Medium","gaps":["Specificity of actin inhibitors for WHAMM-driven pathway not established","Relationship between WHAMM's autophagy and apoptosis functions in tubule cells unresolved"]},{"year":null,"claim":"How WHAMM's competing membrane-targeting, microtubule-binding, Rab1-inhibition, and Arp2/3-activation states are switched to select between autophagy, lysosome reformation, and apoptosis remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified regulatory model integrating the conformational gating, phosphoinositide selection, and Rab/Rho G-protein inputs","Mechanism partitioning pro-autophagy versus pro-apoptotic WHAMM activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3,4,5,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["ACTR2/ACTR3 (ARP2/3 COMPLEX)","TUBB/TUBULIN","RAB1","RHOD","ACTB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TF30","full_name":"WASP homolog-associated protein with actin, membranes and microtubules","aliases":["WAS protein homology region 2 domain-containing protein 1","WH2 domain-containing protein 1"],"length_aa":809,"mass_kda":90.9,"function":"Acts as a nucleation-promoting factor (NPF) that stimulates Arp2/3-mediated actin polymerization both at the Golgi apparatus and along tubular membranes. Its activity in membrane tubulation requires F-actin and interaction with microtubules. Proposed to use coordinated actin-nucleating and microtubule-binding activities of distinct WHAMM molecules to drive membrane tubule elongation; when MT-bound can recruit and remodel membrane vesicles but is prevented to activate the Arp2/3 complex. Involved as a regulator of Golgi positioning and morphology. Participates in vesicle transport between the reticulum endoplasmic and the Golgi complex. Required for RhoD-dependent actin reorganization such as in cell adhesion and cell migration","subcellular_location":"Cytoplasm; Endoplasmic reticulum-Golgi intermediate compartment; Cytoplasmic vesicle membrane; Golgi apparatus, cis-Golgi network","url":"https://www.uniprot.org/uniprotkb/Q8TF30/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WHAMM","classification":"Not Classified","n_dependent_lines":145,"n_total_lines":1208,"dependency_fraction":0.12003311258278146},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WHAMM","total_profiled":1310},"omim":[{"mim_id":"616144","title":"WD REPEAT-CONTAINING PROTEIN 73; WDR73","url":"https://www.omim.org/entry/616144"},{"mim_id":"612393","title":"WAS PROTEIN HOMOLOG ASSOCIATED WITH ACTIN, GOLGI MEMBRANES, AND MICROTUBULES; WHAMM","url":"https://www.omim.org/entry/612393"},{"mim_id":"251300","title":"GALLOWAY-MOWAT SYNDROME 1; GAMOS1","url":"https://www.omim.org/entry/251300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":29.4}],"url":"https://www.proteinatlas.org/search/WHAMM"},"hgnc":{"alias_symbol":["KIAA1971","WHAMM1"],"prev_symbol":["WHDC1"]},"alphafold":{"accession":"Q8TF30","domains":[{"cath_id":"-","chopping":"182-372","consensus_level":"medium","plddt":92.9816,"start":182,"end":372},{"cath_id":"3.30.1520","chopping":"29-61_77-115_141-180","consensus_level":"high","plddt":80.8468,"start":29,"end":180},{"cath_id":"1.10.287","chopping":"382-420_457-508","consensus_level":"medium","plddt":93.7576,"start":382,"end":508}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TF30","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TF30-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TF30-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WHAMM","jax_strain_url":"https://www.jax.org/strain/search?query=WHAMM"},"sequence":{"accession":"Q8TF30","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TF30.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TF30/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TF30"}},"corpus_meta":[{"pmid":"20888769","id":"PMC_20888769","title":"WASH, WHAMM and JMY: regulation of Arp2/3 complex and beyond.","date":"2010","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20888769","citation_count":151,"is_preprint":false},{"pmid":"26096974","id":"PMC_26096974","title":"WHAMM Directs the Arp2/3 Complex to the ER for Autophagosome Biogenesis through an Actin Comet Tail Mechanism.","date":"2015","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/26096974","citation_count":108,"is_preprint":false},{"pmid":"31420534","id":"PMC_31420534","title":"WHAMM initiates autolysosome tubulation by promoting actin polymerization on autolysosomes.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31420534","citation_count":60,"is_preprint":false},{"pmid":"22316129","id":"PMC_22316129","title":"Evolution of the eukaryotic ARP2/3 activators of the WASP family: WASP, WAVE, WASH, and WHAMM, and the proposed new family members WAWH and WAML.","date":"2012","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/22316129","citation_count":53,"is_preprint":false},{"pmid":"26823012","id":"PMC_26823012","title":"Rab1 recruits WHAMM during membrane remodeling but limits actin nucleation.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26823012","citation_count":28,"is_preprint":false},{"pmid":"23027905","id":"PMC_23027905","title":"Structural insights into WHAMM-mediated cytoskeletal coordination during membrane remodeling.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23027905","citation_count":28,"is_preprint":false},{"pmid":"26291929","id":"PMC_26291929","title":"WHAMM links actin assembly via the Arp2/3 complex to autophagy.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/26291929","citation_count":24,"is_preprint":false},{"pmid":"28720660","id":"PMC_28720660","title":"An Amish founder mutation disrupts a PI(3)P-WHAMM-Arp2/3 complex-driven autophagosomal remodeling pathway.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/28720660","citation_count":22,"is_preprint":false},{"pmid":"23160625","id":"PMC_23160625","title":"WHAMM is required for meiotic spindle migration and asymmetric cytokinesis in mouse oocytes.","date":"2012","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23160625","citation_count":18,"is_preprint":false},{"pmid":"33872315","id":"PMC_33872315","title":"The actin nucleation factors JMY and WHAMM enable a rapid Arp2/3 complex-mediated intrinsic pathway of apoptosis.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33872315","citation_count":13,"is_preprint":false},{"pmid":"28351611","id":"PMC_28351611","title":"Structural Insights of WHAMM's Interaction with Microtubules by Cryo-EM.","date":"2017","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28351611","citation_count":11,"is_preprint":false},{"pmid":"33036756","id":"PMC_33036756","title":"An actin-WHAMM interaction linking SETD2 and autophagy.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33036756","citation_count":8,"is_preprint":false},{"pmid":"33397186","id":"PMC_33397186","title":"WHAMM is essential for spindle formation and spindle actin polymerization in maturing mouse oocytes.","date":"2021","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/33397186","citation_count":7,"is_preprint":false},{"pmid":"38598293","id":"PMC_38598293","title":"WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.","date":"2024","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/38598293","citation_count":4,"is_preprint":false},{"pmid":"40138314","id":"PMC_40138314","title":"The actin and microtubule network regulator WHAMM is identified as a key kidney disease risk gene.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40138314","citation_count":2,"is_preprint":false},{"pmid":"38328079","id":"PMC_38328079","title":"WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38328079","citation_count":1,"is_preprint":false},{"pmid":"39564703","id":"PMC_39564703","title":"WHAMM Inhibits Type II Alveolar Epithelial Cell EMT by Mediating Autophagic Degradation of TGF-β1 in Bronchopulmonary Dysplasia.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39564703","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9138,"output_tokens":3408,"usd":0.039267,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10980,"output_tokens":3604,"usd":0.0725,"stage2_stop_reason":"end_turn"},"total_usd":0.111767,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"WHAMM binds to the outer surface of microtubule protofilaments via a novel interaction between its central coiled-coil region and tubulin heterodimers; upon MT binding, the N-terminal membrane-binding domain is exposed at the MT periphery to recruit and remodel vesicles into tubular structures, while MT binding simultaneously masks the C-terminal WCA domain and prevents actin nucleation activity.\",\n      \"method\": \"Cryo-electron microscopy, biophysical and biochemical approaches (in vitro binding assays, domain mutagenesis)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with biochemical/biophysical validation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23027905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WHAMM interacts with αβ-tubulin through a small peptide motif (MT-binding motif, MBM) within its MT-binding domain; cryo-EM reconstruction revealed the atomic-level arrangement of MBM around MTs, and chemical cross-linking/mass spectrometry confirmed a conformational switch of the MBM between the non-MT-bound and MT-bound states.\",\n      \"method\": \"Cryo-electron microscopy, chemical cross-linking, mass spectrometry\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with orthogonal biochemical validation (cross-linking MS), single lab but multiple rigorous methods\",\n      \"pmids\": [\"28351611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Active Rab1 (GTP-bound) recruits WHAMM to dynamic tubulovesicular structures and a prenylated active form of Rab1 binds directly to an N-terminal domain of WHAMM in vitro; paradoxically, Rab1 binding inhibits WHAMM-mediated Arp2/3-dependent actin assembly, representing a strategy where a Rab G-protein recruits the nucleation machinery but dampens its activity.\",\n      \"method\": \"Co-localization in fibroblasts, in vitro direct binding assay (prenylated Rab1 pulldown with N-terminal WHAMM domain), actin assembly assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro binding assay plus cell-based functional readout (tubule formation, actin assembly), two orthogonal methods in one study\",\n      \"pmids\": [\"26823012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WHAMM directs Arp2/3 complex activity at the ER to drive autophagosome biogenesis via an actin comet-tail mechanism; WHAMM puncta colocalize and comigrate with autophagy markers LC3, DFCP1, and p62, and knockdown of WHAMM or mutagenesis blocking its interaction with Arp2/3 complex reduces autophagosome size and number.\",\n      \"method\": \"Live-cell imaging, siRNA knockdown, Arp2/3-interaction mutagenesis, pharmacological inhibition of actin polymerization and Arp2/3 complex\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (KD, mutagenesis, pharmacology, live imaging) replicated across two companion papers (PMID 26096974, 26291929)\",\n      \"pmids\": [\"26096974\", \"26291929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"WHAMM is required for autophagic lysosome reformation (ALR): it is recruited to the autolysosome membrane through specific binding to PI(4,5)P2, then promotes assembly of an actin scaffold on the autolysosome surface to drive tubulation. WHAMM knockout causes accumulation of enlarged autolysosomes during prolonged starvation.\",\n      \"method\": \"WHAMM knockout, lipid-binding assay (PI(4,5)P2 interaction), live-cell imaging of autolysosome tubulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with specific cellular phenotype, direct lipid-binding assay, and live imaging, multiple orthogonal methods in one study\",\n      \"pmids\": [\"31420534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WHAMM binds to PI(3)P and promotes actin nucleation at nascent autophagosomes; patient cells harboring a WHAMM founder mutation show cytoskeletal irregularities and severe autophagy defects, and reintroduction of wild-type WHAMM restores autophagosomal biogenesis; WHAMM inactivation in healthy cells inhibits LC3 lipidation and clearance of ubiquitinated aggregates.\",\n      \"method\": \"Patient cell complementation, WHAMM inactivation (siRNA/mutation), PI(3)P binding assay, LC3 lipidation assay, ubiquitinated aggregate clearance assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complementation in patient cells plus multiple biochemical readouts, single lab but orthogonal methods\",\n      \"pmids\": [\"28720660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WHAMM and its binding partner the Arp2/3 complex control autophagosomal membrane closure and cargo receptor recruitment in mouse fibroblasts and human proximal tubule cells; loss of WHAMM causes accumulation of lipidated LC3 in kidney tissue and structural abnormalities of the proximal tubule affecting nutrient reabsorption in male knockout mice.\",\n      \"method\": \"WHAMM knockout mice (physiological phenotype), autophagy flux assays (LC3 lipidation), membrane closure assays in cell lines\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with defined phenotype plus cell-based mechanistic assays, peer-reviewed publication\",\n      \"pmids\": [\"38598293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WHAMM promotes the intrinsic (mitochondrial) apoptosis pathway in a p53-dependent manner, enhancing mitochondrial permeabilization, initiator caspase cleavage, and executioner caspase activation; actin filaments assembled via Arp2/3 complex appear in cytoplasmic territories containing cytochrome c clusters and active caspase-3; RhoD (a WHAMM-interacting G-protein) opposes this cell death pathway.\",\n      \"method\": \"WASP-family gene inactivation (CRISPR/siRNA), caspase cleavage assays, cytochrome c release assay, live-cell imaging, RhoD depletion/deletion epistasis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple biochemical readouts and epistasis (RhoD), single lab\",\n      \"pmids\": [\"33872315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WHAMM controls actin-mediated cytochrome c release from mitochondria and ASC speck formation in kidney tubule cells, connecting WHAMM-driven actin dynamics to cell death pathways; pharmacological inhibition of actin dynamics mitigates kidney disease in cisplatin, folic acid, and UUO experimental models.\",\n      \"method\": \"Genetic deletion of Whamm in mice (disease models), in vitro cell studies (cytochrome c release, ASC speck assay), pharmacological actin inhibition\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse disease models plus cell-based mechanistic assays, single lab, multiple readouts\",\n      \"pmids\": [\"40138314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"WHAMM localizes to the meiotic spindle in mouse oocytes (after meiosis resumption, not at GV stage), and depletion by siRNA causes failure of spindle migration, disruption of actin cap formation, asymmetric cytokinesis failure, and decreased first polar body extrusion.\",\n      \"method\": \"Immunostaining, siRNA microinjection in mouse oocytes, nocodazole/taxol treatment\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, siRNA knockdown with cellular phenotype but limited mechanistic resolution of pathway\",\n      \"pmids\": [\"23160625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WHAMM co-localizes with the actin cage permeating the meiotic spindle in mouse oocytes; depletion impairs spindle formation, displaces the MTOC, disrupts spindle actin formation, and causes chromosomal aneuploidy and abnormal asymmetric division; BFA treatment disperses WHAMM localization, linking ER-to-Golgi trafficking to WHAMM's spindle function.\",\n      \"method\": \"siRNA knockdown in mouse oocytes, immunofluorescence, brefeldin A (BFA) treatment\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, KD with cellular phenotypes but no direct pathway reconstitution\",\n      \"pmids\": [\"33397186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WHAMM's interaction with actin is required for initiation of autophagy; in SETD2-null cells the WHAMM–actin interaction is reduced, leading to autophagy defects; this deficit is rescued by pharmacological induction of actin polymerization (jasplakinolide), indicating that the impaired interaction results from altered actin dynamics rather than direct loss of the SETD2-mediated ActK68me3 mark.\",\n      \"method\": \"Co-immunoprecipitation (WHAMM–actin), SETD2 knockout cells, jasplakinolide rescue, autophagy flux assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with partial mechanistic follow-up, single lab, single publication\",\n      \"pmids\": [\"33036756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WHAMM enhances autophagosomal localization of TGF-β1 and promotes autophagic degradation of TGF-β1 in type II alveolar epithelial cells, thereby suppressing TGF-β1-driven EMT; knockdown of WHAMM causes accumulation of TGF-β1 and increased EMT markers in a hyperoxia-induced BPD model.\",\n      \"method\": \"WHAMM knockdown/overexpression, autophagy flux assays, TGF-β1 colocalization with autophagosome markers, EMT marker analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD/OE with cellular readouts but limited mechanistic resolution of how WHAMM targets TGF-β1 to autophagosomes\",\n      \"pmids\": [\"39564703\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WHAMM is a Wiskott-Aldrich Syndrome protein family nucleation-promoting factor (NPF) that activates the Arp2/3 complex to polymerize branched actin filaments; it binds microtubules via a short peptide motif in its coiled-coil domain (which simultaneously suppresses its actin nucleation activity), recruits membranes through its N-terminal domain (engaging PI(3)P and PI(4,5)P2 on distinct organelles), and functions at the ER/autophagosome interface to drive autophagosome biogenesis, membrane closure, and autophagic lysosome reformation via actin comet-tail formation; it is regulated upstream by Rab1, which recruits WHAMM to tubulovesicular structures but inhibits its nucleation activity, and it additionally participates in intrinsic apoptosis by promoting mitochondrial permeabilization and caspase activation in an Arp2/3-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WHAMM is a Wiskott-Aldrich Syndrome protein family nucleation-promoting factor that activates the Arp2/3 complex to drive branched actin polymerization in service of membrane remodeling, autophagy, and intrinsic apoptosis [#3, #5]. Its central coiled-coil region binds the outer surface of microtubule protofilaments through a short MT-binding peptide motif that adopts distinct conformations in the free and MT-bound states; this engagement exposes the N-terminal membrane-binding domain to recruit and tubulate vesicles while simultaneously masking the C-terminal WCA domain to suppress actin nucleation [#0, #1]. WHAMM is recruited to membranes through phosphoinositide engagement—PI(3)P at nascent autophagosomes and PI(4,5)P2 at autolysosomes—and through the GTP-bound G-protein Rab1, which paradoxically recruits the nucleation machinery to tubulovesicular structures while dampening its Arp2/3-dependent actin assembly [#2, #4, #5]. Functionally, WHAMM directs Arp2/3 activity at the ER to nucleate actin comet tails that build autophagosomes, controls autophagosomal membrane closure and cargo receptor recruitment, and drives actin-scaffold-dependent tubulation required for autophagic lysosome reformation; its loss impairs LC3 lipidation, autophagic flux, and clearance of ubiquitinated aggregates [#3, #4, #5, #6]. Independently, WHAMM promotes the intrinsic mitochondrial apoptosis pathway in an Arp2/3- and p53-dependent manner, enhancing mitochondrial permeabilization, cytochrome c release, and caspase activation, with RhoD opposing this death pathway [#7, #8]. A WHAMM founder mutation in patient cells produces cytoskeletal irregularities and severe autophagy defects rescued by wild-type WHAMM, and Whamm-knockout mice show LC3 accumulation and proximal tubule structural abnormalities [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolving how WHAMM couples microtubules to membrane remodeling established that its coiled-coil binds tubulin while its termini are conformationally gated—MT binding exposes the membrane-binding domain and silences actin nucleation.\",\n      \"evidence\": \"Cryo-EM of WHAMM on microtubules with in vitro binding assays and domain mutagenesis\",\n      \"pmids\": [\"23027905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the in vivo trigger that releases the WCA domain for nucleation\", \"Physiological setting of MT-templated vesicle tubulation not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying WHAMM at the meiotic spindle extended its role beyond interphase trafficking to actin- and microtubule-dependent asymmetric division.\",\n      \"evidence\": \"Immunostaining and siRNA microinjection in mouse oocytes with nocodazole/taxol treatment\",\n      \"pmids\": [\"23160625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking WHAMM to spindle migration\", \"Whether Arp2/3 activation underlies the actin cap defect not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connecting WHAMM to autophagosome biogenesis showed it directs Arp2/3-mediated actin comet tails at the ER, defining a cytoskeletal driver of early autophagy.\",\n      \"evidence\": \"Live-cell imaging, siRNA knockdown, Arp2/3-interaction mutagenesis, and pharmacological actin/Arp2/3 inhibition across two companion papers\",\n      \"pmids\": [\"26096974\", \"26291929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WHAMM is initially targeted to the ER/autophagosome interface not resolved here\", \"Relationship between comet-tail force and membrane shaping not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining Rab1 as an upstream recruiter clarified that a Rab GTPase positions WHAMM on tubulovesicular structures yet restrains its actin-nucleating output.\",\n      \"evidence\": \"Co-localization in fibroblasts, in vitro prenylated-Rab1 binding to N-terminal WHAMM, and actin assembly assays\",\n      \"pmids\": [\"26823012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal relieving Rab1-mediated inhibition unknown\", \"Whether Rab1 regulation operates during autophagy specifically not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping phosphoinositide and tubulin binding plus patient-cell complementation established WHAMM's PI(3)P-dependent membrane recruitment and causal role in human autophagy.\",\n      \"evidence\": \"Cryo-EM of the MT-binding motif with cross-linking MS; patient cell complementation, PI(3)P binding, LC3 lipidation and aggregate-clearance assays\",\n      \"pmids\": [\"28351611\", \"28720660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the disease and full genotype-phenotype relationship not detailed in the corpus\", \"How PI(3)P binding is coordinated with Arp2/3 activation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating WHAMM in autophagic lysosome reformation showed its membrane targeting is lipid-context-specific—PI(4,5)P2 at autolysosomes—driving actin-scaffold tubulation distinct from biogenesis.\",\n      \"evidence\": \"WHAMM knockout, PI(4,5)P2 lipid-binding assay, and live imaging of autolysosome tubulation\",\n      \"pmids\": [\"31420534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WHAMM switches between PI(3)P and PI(4,5)P2 membranes not defined\", \"Force-generation mechanism for tubulation not reconstituted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking WHAMM to intrinsic apoptosis revealed an Arp2/3- and p53-dependent role in mitochondrial permeabilization and caspase activation, with RhoD as an opposing regulator.\",\n      \"evidence\": \"WASP-family gene inactivation (CRISPR/siRNA), caspase and cytochrome c release assays, live imaging, and RhoD epistasis\",\n      \"pmids\": [\"33872315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How actin filaments mechanistically promote mitochondrial permeabilization unclear\", \"RhoD-WHAMM physical interaction in death context not structurally defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In vivo knockout established WHAMM's requirement for autophagosomal membrane closure and cargo receptor recruitment, with physiological consequences in kidney proximal tubule function.\",\n      \"evidence\": \"Whamm knockout mice with LC3 lipidation flux assays and membrane closure assays in cell lines\",\n      \"pmids\": [\"38598293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of closure versus cargo recruitment not separated\", \"Tissue specificity of the phenotype not fully explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending WHAMM's death-promoting role to disease, actin-mediated cytochrome c release and ASC speck formation were connected to experimental kidney injury treatable by actin inhibition.\",\n      \"evidence\": \"Whamm-deletion mouse disease models (cisplatin, folic acid, UUO), cytochrome c and ASC speck assays, pharmacological actin inhibition\",\n      \"pmids\": [\"40138314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity of actin inhibitors for WHAMM-driven pathway not established\", \"Relationship between WHAMM's autophagy and apoptosis functions in tubule cells unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WHAMM's competing membrane-targeting, microtubule-binding, Rab1-inhibition, and Arp2/3-activation states are switched to select between autophagy, lysosome reformation, and apoptosis remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified regulatory model integrating the conformational gating, phosphoinositide selection, and Rab/Rho G-protein inputs\", \"Mechanism partitioning pro-autophagy versus pro-apoptotic WHAMM activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3, 4, 5, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACTR2/ACTR3 (Arp2/3 complex)\", \"TUBB/tubulin\", \"RAB1\", \"RHOD\", \"ACTB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}