Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016477 cell migration	IBA GO_REF:0000033	ACCEPT	Summary: CD2AP promotes actin-linked cell extension and migration as part of its cortical adaptor/scaffold function. Reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that colocalizes with F-actin at ruffles and leading edges, alters actin organization, forms multimeric partner complexes, and links membrane or junctional proteins to the actin cytoskeleton.
GO:0030674 protein-macromolecule adaptor activity	IBA GO_REF:0000033	ACCEPT	Summary: CD2AP is a membrane- and junction-associated adaptor/scaffold that links partner proteins to actin-rich cortical and endosomal compartments. Reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that colocalizes with F-actin at ruffles and leading edges, alters actin organization, forms multimeric partner complexes, and links membrane or junctional proteins to the actin cytoskeleton.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0007015 actin filament organization	IBA GO_REF:0000033	ACCEPT	Summary: CD2AP directly supports actin cytoskeleton organization and acts in actin-rich ruffles, cell extensions, and epithelial junction remodeling. Reason: Retain as core because the original CMS/CD2AP study and later junction work support CD2AP as an actin-associated scaffold that regulates actin arrangement, cell extensions, and junctional actin remodeling.
GO:0031982 vesicle	IBA GO_REF:0000033	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0031252 cell leading edge	IBA GO_REF:0000033	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0001726 ruffle	IEA GO_REF:0000044	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0032991 protein-containing complex	IEA GO_REF:0000117	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0070161 anchoring junction	IEA GO_REF:0000044	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005515 protein binding	IPI PMID:17020880 Atypical polyproline recognition by the CMS N-terminal Src h...	MODIFY	Summary: The cited interaction is compatible with CD2AP scaffold biology, but generic protein binding is too broad for the actual molecular role. Reason: Generic protein binding does not capture CD2AP function; the informative biology is SH3/proline-rich partner recognition, adaptor/scaffold activity, actin association, or specific junction/endosomal complex participation. Proposed replacements: protein-macromolecule adaptor activity
GO:0005515 protein binding	IPI PMID:17474147 Systematic identification of SH3 domain-mediated human prote...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:17853893 Human ESCRT and ALIX proteins interact with proteins of the ...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:19380743 Charting the molecular network of the drug target Bcr-Abl.	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:21706016 Selected reaction monitoring mass spectrometry reveals the d...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:21822214 The B-cell antigen receptor signals through a preformed tran...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:22662192 IQGAP1 interacts with components of the slit diaphragm compl...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:23663663 Multimeric and differential binding of CIN85/CD2AP with two ...	MODIFY	Summary: The cited interaction is compatible with CD2AP scaffold biology, but generic protein binding is too broad for the actual molecular role. Reason: Generic protein binding does not capture CD2AP function; the informative biology is SH3/proline-rich partner recognition, adaptor/scaffold activity, actin association, or specific junction/endosomal complex participation. Proposed replacements: protein-macromolecule adaptor activity
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:32552912 Upregulation of RIN3 induces endosomal dysfunction in Alzhei...	MODIFY	Summary: The cited interaction is compatible with CD2AP scaffold biology, but generic protein binding is too broad for the actual molecular role. Reason: Generic protein binding does not capture CD2AP function; the informative biology is SH3/proline-rich partner recognition, adaptor/scaffold activity, actin association, or specific junction/endosomal complex participation. Proposed replacements: protein-macromolecule adaptor activity
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0042802 identical protein binding	IPI PMID:17020880 Atypical polyproline recognition by the CMS N-terminal Src h...	ACCEPT	Summary: Structural and biochemical evidence supports multimerization of CD2AP/CMS SH3-domain complexes, consistent with homotypic/multimeric scaffold assembly. Reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that colocalizes with F-actin at ruffles and leading edges, alters actin organization, forms multimeric partner complexes, and links membrane or junctional proteins to the actin cytoskeleton.
GO:0042802 identical protein binding	IPI PMID:31413325 HENA, heterogeneous network-based data set for Alzheimer's d...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0002102 podosome	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Podosome localization is plausible for an actin-rich adhesion scaffold but is not the central CD2AP function established by the strongest evidence. Reason: Keep as non-core because podosomes are an actin-rich adhesion context related to CD2AP cytoskeletal biology but are less central than ruffles, junctions, slit diaphragm, and endosomal adaptor functions.
GO:0003779 actin binding	IEA GO_REF:0000107	ACCEPT	Summary: CD2AP is an actin-associated scaffold, and actin/actin-filament binding is consistent with the original CMS/CD2AP functional evidence and later CapZ-linked junction work. Reason: Retain as core because the original CMS/CD2AP study and later junction work support CD2AP as an actin-associated scaffold that regulates actin arrangement, cell extensions, and junctional actin remodeling.
GO:0005641 nuclear envelope lumen	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005737 cytoplasm	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005770 late endosome	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005884 actin filament	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005886 plasma membrane	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005911 cell-cell junction	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0030276 clathrin binding	IEA GO_REF:0000107	ACCEPT	Summary: CD2AP/CIN85-family adaptor biology supports vesicle, late-endosome, TGN, and clathrin-linked trafficking annotations, with Alzheimer-context evidence for RIN3/BIN1/CD2AP early-endosome recruitment. Reason: Retain as core or near-core because CD2AP is an endocytic adaptor family member that couples cargo trafficking to the cytoskeleton and participates in early-endosomal/receptor-trafficking contexts.
GO:0030424 axon	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0030425 dendrite	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0030426 growth cone	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0031594 neuromuscular junction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0031982 vesicle	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0032588 trans-Golgi network membrane	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0036057 slit diaphragm	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0036312 phosphatidylinositol 3-kinase regulatory subunit binding	IEA GO_REF:0000107	ACCEPT	Summary: CD2AP proline-rich sequences bind signaling SH3-domain partners including the p85 regulatory subunit of phosphatidylinositol 3-kinase, fitting its adaptor role. Reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that colocalizes with F-actin at ruffles and leading edges, alters actin organization, forms multimeric partner complexes, and links membrane or junctional proteins to the actin cytoskeleton.
GO:0043005 neuron projection	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0050808 synapse organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0051015 actin filament binding	IEA GO_REF:0000107	ACCEPT	Summary: CD2AP is an actin-associated scaffold, and actin/actin-filament binding is consistent with the original CMS/CD2AP functional evidence and later CapZ-linked junction work. Reason: Retain as core because the original CMS/CD2AP study and later junction work support CD2AP as an actin-associated scaffold that regulates actin arrangement, cell extensions, and junctional actin remodeling.
GO:0071944 cell periphery	IEA GO_REF:0000107	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0005886 plasma membrane	IDA GO_REF:0000052	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0070161 anchoring junction	EXP PMID:22891260 Epithelial junction formation requires confinement of Cdc42 ...	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0030424 axon	ISS PMID:32552912 Upregulation of RIN3 induces endosomal dysfunction in Alzhei...	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0030425 dendrite	ISS PMID:32552912 Upregulation of RIN3 induces endosomal dysfunction in Alzhei...	KEEP AS NON CORE	Summary: Neuronal projection or synapse context is plausible in Alzheimer/endosomal models but is not the primary defining activity of CD2AP. Reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model evidence, but the strongest conserved function remains SH3-mediated adaptor/scaffold activity at actin-rich membrane, junction, and endosomal structures.
GO:0050714 positive regulation of protein secretion	IMP PMID:27044754 FRMD4A-cytohesin signaling modulates the cellular release of...	UNDECIDED	Summary: The tau-secretion paper is abstract-only in the cache and the abstract foregrounds FRMD4A rather than CD2AP, so the CD2AP-specific experimental basis cannot be verified here. Reason: Use UNDECIDED rather than REMOVE because this is an experimental annotation and the cached abstract does not expose the CD2AP-specific evidence that curators may have used from the full text.
GO:0045296 cadherin binding	HDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:22891260 Epithelial junction formation requires confinement of Cdc42 ...	MODIFY	Summary: The cited interaction is compatible with CD2AP scaffold biology, but generic protein binding is too broad for the actual molecular role. Reason: Generic protein binding does not capture CD2AP function; the informative biology is SH3/proline-rich partner recognition, adaptor/scaffold activity, actin association, or specific junction/endosomal complex participation. Proposed replacements: protein-macromolecule adaptor activity
GO:0007015 actin filament organization	IMP PMID:22891260 Epithelial junction formation requires confinement of Cdc42 ...	ACCEPT	Summary: CD2AP directly supports actin cytoskeleton organization and acts in actin-rich ruffles, cell extensions, and epithelial junction remodeling. Reason: Retain as core because the original CMS/CD2AP study and later junction work support CD2AP as an actin-associated scaffold that regulates actin arrangement, cell extensions, and junctional actin remodeling.
GO:0051058 negative regulation of small GTPase mediated signal transduction	IMP PMID:22891260 Epithelial junction formation requires confinement of Cdc42 ...	ACCEPT	Summary: CD2AP is part of a SH3BP1/JACOP/CapZ junctional scaffold required for normal Cdc42 signaling, actin remodeling, and epithelial junction formation. Reason: Retain as core because full-text evidence shows CD2AP in a junctional scaffold with SH3BP1/JACOP and CapZ; CD2AP depletion impaired junctional SH3BP1 targeting, Cdc42 control, and junction formation.
GO:0005515 protein binding	IPI PMID:18641129 Differential requirements for Alix and ESCRT-III in cytokine...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: This annotation comes from generic interaction, high-throughput, dataset, or low-specificity localization evidence and does not define CD2AP core molecular function. Reason: Mark as over-annotated because this high-throughput or generic interaction/localization evidence is less informative than CD2AP adaptor, actin-cytoskeleton, endosomal, and junctional terms.
GO:0005515 protein binding	IPI PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	MODIFY	Summary: The cited interaction is compatible with CD2AP scaffold biology, but generic protein binding is too broad for the actual molecular role. Reason: Generic protein binding does not capture CD2AP function; the informative biology is SH3/proline-rich partner recognition, adaptor/scaffold activity, actin association, or specific junction/endosomal complex participation. Proposed replacements: protein-macromolecule adaptor activity actin filament binding
GO:0017124 SH3 domain binding	IPI PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	ACCEPT	Summary: CD2AP has proline-rich regions that bind SH3-domain-containing partners, supporting its scaffold/adaptor function. Reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that colocalizes with F-actin at ruffles and leading edges, alters actin organization, forms multimeric partner complexes, and links membrane or junctional proteins to the actin cytoskeleton.
GO:0001726 ruffle	IDA PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0031941 filamentous actin	IDA PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0007165 signal transduction	NAS PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	MODIFY	Summary: The 1999 paper supports CD2AP as a scaffold/adaptor involved in cytoskeletal rearrangement, but broad signal transduction is not specific enough. Reason: Replace broad signal transduction with the more specific adaptor and actin-organization functions supported by the same study. Proposed replacements: protein-macromolecule adaptor activity actin filament organization
GO:0005200 structural constituent of cytoskeleton	TAS PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	MODIFY	Summary: CD2AP is an actin-associated scaffold, but structural constituent of cytoskeleton overstates the evidence compared with adaptor/actin-binding function. Reason: Replace structural constituent of cytoskeleton with CD2AP adaptor activity and actin filament binding, which better describe the evidence. Proposed replacements: protein-macromolecule adaptor activity actin filament binding
GO:0005737 cytoplasm	TAS PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0006930 substrate-dependent cell migration, cell extension	TAS PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	ACCEPT	Summary: CD2AP directly supports actin cytoskeleton organization and acts in actin-rich ruffles, cell extensions, and epithelial junction remodeling. Reason: Retain as core because the original CMS/CD2AP study and later junction work support CD2AP as an actin-associated scaffold that regulates actin arrangement, cell extensions, and junctional actin remodeling.
GO:0015629 actin cytoskeleton	TAS PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	ACCEPT	Summary: This location matches CD2AP localization to cytoplasm, cortical actin structures, ruffles/leading edges, vesicles/endosomal compartments, plasma membrane, and junctional/slit-diaphragm sites. Reason: Retain as core because CD2AP acts at actin-rich membrane and junction compartments, including ruffles, leading edges, cell-cell/anchoring junctions, podocyte slit diaphragm context, and vesicle/endosomal sites.
GO:0065003 protein-containing complex assembly	TAS PMID:10339567 CMS: an adapter molecule involved in cytoskeletal rearrangem...	ACCEPT	Summary: CD2AP directly supports actin cytoskeleton organization and acts in actin-rich ruffles, cell extensions, and epithelial junction remodeling. Reason: Retain as core because the original CMS/CD2AP study and later junction work support CD2AP as an actin-associated scaffold that regulates actin arrangement, cell extensions, and junctional actin remodeling.

Core Functions

CD2AP functions as a multivalent SH3-domain scaffold/adaptor that links membrane-associated partner proteins and signaling complexes to actin-rich cortical structures, supporting actin organization, cell extension, and partner-complex assembly.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

actin filament organization cell migration substrate-dependent cell migration, cell extension protein-containing complex assembly

Cellular Locations:

cytoplasm actin cytoskeleton ruffle cell leading edge plasma membrane

Supporting Evidence:

PMID:10339567
functions as a scaffolding molecule with a specialized role in regulation of the actin cytoskeleton
PMID:10339567
colocalizes with F-actin and p130(Cas) to membrane ruffles and leading edges of cells
PMID:17020880
can mediate multimerization of N-terminal CMS SH3 domains

CD2AP associates with F-actin-rich cortical and junctional structures and helps coordinate actin remodeling through scaffolded complexes that include CapZ and SH3BP1/JACOP.

Molecular Function:

actin filament binding

Directly Involved In:

actin filament organization negative regulation of small GTPase mediated signal transduction

Cellular Locations:

actin cytoskeleton actin filament cell-cell junction anchoring junction slit diaphragm

Supporting Evidence:

PMID:22891260
both were required for normal Cdc42 signaling and junction formation
PMID:22891260
submembrane actin cytoskeleton and binds and regulates CapZ
PMID:10339567
Ectopic expression of CMS in COS-7 cells resulted in alteration in arrangement of the actin cytoskeleton
file:human/CD2AP/CD2AP-deep-research-falcon.md
CD2AP functions as an adapter protein that anchors slit diaphragm proteins (nephrin, podocin) to actin filaments of podocyte foot processes

CD2AP also acts in endocytic and receptor-trafficking modules, coupling cargo and signaling complexes to cytoskeletal machinery at vesicles, endosomes, and trans-Golgi network-associated membranes.

Molecular Function:

protein-macromolecule adaptor activity

Directly Involved In:

protein-containing complex assembly

Cellular Locations:

vesicle late endosome trans-Golgi network membrane

Supporting Evidence:

PMID:17020880
trafficking with the cytoskeleton
PMID:17020880
required for an efficient internalization of cell surface receptors
PMID:32552912
RIN3 recruited BIN1(bridging integrator 1) and CD2AP (CD2 associated protein)

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:10339567

CMS: an adapter molecule involved in cytoskeletal rearrangements.

PMID:17020880

Atypical polyproline recognition by the CMS N-terminal Src homology 3 domain.

PMID:17474147

Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening.

PMID:17853893

Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis.

PMID:18641129

Differential requirements for Alix and ESCRT-III in cytokinesis and HIV-1 release.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19380743

Charting the molecular network of the drug target Bcr-Abl.

PMID:21706016

Selected reaction monitoring mass spectrometry reveals the dynamics of signaling through the GRB2 adaptor.

PMID:21822214

The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22662192

IQGAP1 interacts with components of the slit diaphragm complex in podocytes and is involved in podocyte migration and permeability in vitro.

PMID:22891260

Epithelial junction formation requires confinement of Cdc42 activity by a novel SH3BP1 complex.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:23663663

Multimeric and differential binding of CIN85/CD2AP with two atypical proline-rich sequences from CD2 and Cbl-b*.

PMID:25036637

A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.

PMID:25468996

E-cadherin interactome complexity and robustness resolved by quantitative proteomics.

PMID:27044754

FRMD4A-cytohesin signaling modulates the cellular release of tau.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:31413325

HENA, heterogeneous network-based data set for Alzheimer's disease.

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:32552912

Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's disease.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

file:human/CD2AP/CD2AP-deep-research-falcon.md

Falcon deep research report for CD2AP

Falcon deep research corroborates the review's core picture of CD2AP as a multi-SH3 scaffold/adaptor that links membrane and slit-diaphragm partner proteins to the actin cytoskeleton.

"CD2AP functions primarily as a scaffolding/adapter protein that coordinates protein-protein interactions through its structural domains"

Suggested Experiments

Experiment: Edit or rescue CD2AP SH3 domains, proline-rich region, coiled-coil region, and actin-associated C-terminal region in epithelial cells and podocyte models, then measure partner recruitment, junction assembly, slit-diaphragm marker organization, Cdc42 spatial activity, and actin dynamics.

Hypothesis: CD2AP scaffold domains separably control partner multimerization, actin association, and junction/slit-diaphragm organization.

Type: domain-resolved junction and actin scaffold rescue assay

Experiment: Perturb CD2AP, RIN3, and BIN1 singly and in combination in primary neurons or induced neuronal cultures, then quantify APP/BACE1 trafficking, early-endosome recruitment, axonal transport, APP C-terminal fragments, and tau secretion.

Hypothesis: The Alzheimer-associated RIN3-BIN1-CD2AP module affects APP and tau-related phenotypes through endosomal trafficking rather than through a generic protein-binding function.

Type: neuronal endosomal trafficking and APP-processing assay

Deep Research

Falcon

(CD2AP-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 22 citations 2 artifacts 2026-06-21T07:22:38.453100

Edison artifact artifact-00 (text/markdown)

Edison artifact artifact-01 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: CD2AP (CD2-Associated Protein)

Gene and Protein Identity

CD2AP (CD2-associated protein, UniProt Q9Y5K6) is a human gene encoding a 639-amino acid multifunctional scaffolding and adapter protein (mehrabipour2023asystematiccompilation pages 1-2, zhang2024cd2appromotesthe pages 1-2). The protein is characterized by three consecutive SH3 (Src Homology 3) domains and proline-rich regions, which mediate diverse protein-protein interactions (mehrabipour2023asystematiccompilation pages 1-2, arden2024themyo1finteractome pages 1-3). CD2AP was initially identified as an SH3-containing protein that binds to the CD2 receptor via its cytoplasmic domain (fitzsimons2024cd2apiscoexpressed pages 1-3).

Primary Molecular Function and Structure

Core Adapter/Scaffold Function

CD2AP functions primarily as a scaffolding/adapter protein that coordinates protein-protein interactions through its structural domains (zhang2024cd2appromotesthe pages 1-2, ha2013rolesofadaptor pages 1-2). The three SH3 domains recognize and bind proline-rich motifs (PxxP consensus sequences) in partner proteins, enabling CD2AP to assemble multiprotein complexes (mehrabipour2023asystematiccompilation pages 1-2). This modular architecture allows CD2AP to serve as a hub where signaling pathway components converge, and when the required combination of interactions are formed, corresponding downstream signaling cascades are activated (fitzsimons2024cd2apiscoexpressed pages 1-3).

Binding Specificity and Partner Proteins

The SH3 domains of CD2AP mediate multivalent proline-rich motif interactions with numerous binding partners (arden2024themyo1finteractome pages 1-3, mehrabipour2023asystematiccompilation pages 1-2). Recent proximity labeling studies identified a distinct SH3-domain-dependent adaptor module comprising CD2AP, ASAP1, SH3BP2, and SH3KBP1, termed the CASS group of proteins (arden2024themyo1finteractome pages 1-3, arden2024themyo1finteractome pages 3-6). These interactions involve structural modeling-confirmed multivalent binding between proline-rich motifs in partner proteins and the MYO1F SH3 domain, which also associates with CD2AP (arden2024themyo1finteractome pages 1-3).

A comprehensive summary of CD2AP binding partners and their functional roles is provided below:

Binding Partner	Interaction Domain (on CD2AP)	Cellular Context/Location	Functional Role
Nephrin	Primarily C-terminal/adaptor interface; CD2AP functions as a scaffold linking nephrin to downstream cytoskeletal machinery	Podocyte slit diaphragm, lipid raft-associated junctional complex	Couples slit-diaphragm signaling to actin remodeling; helps maintain foot-process architecture and filtration barrier integrity (blaine2020regulationofthe pages 3-5, ha2013rolesofadaptor pages 1-2, swiateckaurban2017endocytictraffickingat pages 1-2)
Podocin	C-terminal region of podocin binds CD2AP scaffold; exact CD2AP subsite not fully resolved in these sources	Podocyte slit diaphragm/lipid rafts	Stabilizes the nephrin–podocin–CD2AP complex and links slit-diaphragm components to the actin cytoskeleton (blaine2020regulationofthe pages 3-5, ha2013rolesofadaptor pages 1-2, swiateckaurban2017endocytictraffickingat pages 1-2)
F-actin / actin cytoskeleton	Direct/functional actin-associating regions outside the SH3 cluster; CD2AP also links actin indirectly through partner proteins	Podocyte foot processes, vesicles, cortical cytoskeleton, phagocytic structures	Structural linkage between membrane complexes and actin; supports cytoskeletal organization, vesicle trafficking, and cell shape control (blaine2020regulationofthe pages 3-5, tolvanen2015lackofcd2ap pages 1-4, zhang2024cd2appromotesthe pages 1-2)
TrkA	Scaffold interface enabling assembly of receptor-signaling complexes; specific residue-level site not defined here	Neurons, especially NGF-responsive sensory and basal forebrain cholinergic neurons	Coordinates NGF-dependent trophic signaling and receptor-linked retrograde signaling/endocytosis (fitzsimons2024cd2apiscoexpressed pages 1-3)
Rab5	Endosomal/scaffold association; specific CD2AP subdomain not defined here	Rab5-positive endosomes in neurons; endocytic compartments	Supports Rab5-mediated endocytosis and retrograde transport/signaling from internalized receptor complexes (fitzsimons2024cd2apiscoexpressed pages 1-3)
PI3K p85	Scaffold-binding interface assembling signaling complexes downstream of receptors	Neurons; also broader signaling complexes	Promotes PI3K/Akt pathway coupling downstream of trophic receptors such as TrkA (fitzsimons2024cd2apiscoexpressed pages 1-3)
Clathrin	Complex formation with CD2AP; likely via non-SH3 scaffold regions coordinating vesicle machinery	Perinuclear region, clathrin-coated/recycling vesicles, podocytes	Connects clathrin to actin and supports vesicle sorting/recycling, including Glut4 trafficking (tolvanen2015lackofcd2ap pages 1-4)
Cortactin	Direct/functional interaction outside core SH3 ligand-binding description in these sources	Podocyte actin cytoskeleton/slit diaphragm-associated actin network	Reinforces the link from nephrin/CD2AP complexes to actin assembly and cytoskeletal remodeling (blaine2020regulationofthe pages 3-5)
Synaptopodin	Direct/functional interaction; exact subdomain not specified here	Podocyte foot processes and actin-rich structures	Helps connect slit-diaphragm signaling to actin bundle organization and podocyte structural stability (blaine2020regulationofthe pages 3-5)
ASAP1	SH3-domain-dependent interaction, involving proline-rich motif recognition	Macrophage and microglial podosomes; MYO1F-associated adaptor module	Adaptor in podosomes/phagocytic structures; implicated in actin-rich adhesion and membrane-remodeling complexes (arden2024themyo1finteractome pages 3-6, arden2024themyo1finteractome pages 1-3)
SH3BP2	SH3-domain-dependent interaction, involving proline-rich motif recognition	Immune cells; MYO1F-associated adaptor module	Participates in MYO1F-associated adaptor network in podosomes/phagocytic cups (arden2024themyo1finteractome pages 3-6, arden2024themyo1finteractome pages 1-3)
SH3KBP1 (CIN85)	SH3-domain-dependent interaction, involving proline-rich motif recognition	Immune cells; podocytes; phagocytic cups	Component of the CASS adaptor module; linked to endocytosis, actin regulation, and phagocytic structures (arden2024themyo1finteractome pages 3-6, swiateckaurban2017endocytictraffickingat pages 2-3)
GGA2	Complex formation with CD2AP; specific CD2AP site not resolved here	Podocyte trans-Golgi/GSV trafficking pathway	Sorts Glut4 toward storage vesicles and supports insulin-responsive glucose transporter trafficking (tolvanen2015lackofcd2ap pages 1-4)
TRIM5	Interaction site not mapped in the retrieved context	Glioblastoma cells	Stabilizes/promotes TRIM5-associated NF-κB signaling, enhancing malignant phenotypes in GBM models (zhang2024cd2appromotesthe pages 1-2)

Table: This table summarizes major experimentally discussed CD2AP interaction partners, the CD2AP region implicated where available, the cellular context, and the functional consequence of each interaction. It is useful for linking CD2AP's scaffold architecture to specific pathways in podocytes, neurons, immune cells, and cancer.

Subcellular Localization

CD2AP exhibits cell type-specific subcellular localization patterns that reflect its diverse functional roles (arden2024themyo1finteractome pages 3-6, blaine2020regulationofthe pages 3-5, fitzsimons2024cd2apiscoexpressed pages 1-3):

Cell Type	Subcellular Location	Key Associated Proteins at that Location	Functional Significance
Podocytes	Slit diaphragm at foot processes; lipid raft-associated junctional complex	Nephrin, podocin, Neph1, ZO-1, actin/cortical cytoskeleton	Links slit-diaphragm receptors to the actin cytoskeleton, helping maintain foot-process architecture, filtration barrier integrity, and slit-diaphragm signaling (blaine2020regulationofthe pages 3-5, ha2013rolesofadaptor pages 1-2, swiateckaurban2017endocytictraffickingat pages 1-2)
Podocytes	Endocytic vesicles and endosomal/lysosomal compartments; perinuclear trafficking region	Clathrin, GGA2, Glut4, IRAP, sortilin, Rab5	Supports endosomal sorting, vesicle recycling, and cargo trafficking, including insulin-responsive Glut4 trafficking and nephrin/podocin turnover (tolvanen2015lackofcd2ap pages 1-4, swiateckaurban2017endocytictraffickingat pages 2-3, tian2022podocyteendocytosisin pages 1-2)
Podocytes	Focal adhesion- and actin-associated regions in foot processes	F-actin, cortactin, synaptopodin, α-actinin-4	Couples junctional and membrane signals to actin remodeling, podocyte shape control, and structural stability under mechanical stress (blaine2020regulationofthe pages 3-5, blaine2020regulationofthe pages 1-3)
Neurons (general/adult brain)	Pre-synaptic terminals and neuronal processes	Synaptic proteostasis-related proteins; endocytic machinery	Recent work indicates CD2AP contributes to neuronal structure, synaptic homeostasis, and plasticity; presynaptic localization is consistent with a role in trafficking/signaling at nerve terminals (fitzsimons2024cd2apiscoexpressed pages 1-3)
Basal forebrain cholinergic neurons	Soma and cholinergic projections; Rab5-decorated endosomes	Rab5, TrkA, PI3K p85	Enriched in NGF-responsive cholinergic neurons, where it is positioned to coordinate retrograde trophic signaling and Rab5-mediated endocytosis relevant to neuronal maintenance and Alzheimer’s disease biology (fitzsimons2024cd2apiscoexpressed pages 1-3)
Immune cells (macrophages, microglia)	Podosomes	MYO1F, ASAP1, SH3BP2, SH3KBP1	Colocalization in actin-rich podosomes supports a role in adhesion, membrane remodeling, and actin-dependent immune cell motility/function (arden2024themyo1finteractome pages 3-6, arden2024themyo1finteractome pages 1-3)
Immune cells (macrophages, microglia)	Phagocytic cups	MYO1F, SH3KBP1, ASAP1	Localization at phagocytic cups indicates participation in phagocytosis-related membrane–cytoskeleton coupling and cup dynamics, especially in myeloid cells and disease-associated microglia (arden2024themyo1finteractome pages 3-6, arden2024themyo1finteractome pages 1-3)
General endocytic compartments across cell types	Plasma membrane-associated endocytic sites, clathrin-linked vesicles, Rab5-positive early endosomes, late endosomal compartments	Clathrin, Rab5, receptor cargoes, actin network components	CD2AP broadly functions at membrane-trafficking interfaces to connect cargo sorting and receptor internalization with actin remodeling and downstream signaling outputs (tolvanen2015lackofcd2ap pages 1-4, fitzsimons2024cd2apiscoexpressed pages 1-3, tian2022podocyteendocytosisin pages 1-2)

Table: This table summarizes where CD2AP localizes in major relevant human cell contexts and what proteins and functions are associated with each location. It is useful for linking CD2AP’s scaffold role to specific subcellular compartments and biological processes.

Podocytes: CD2AP localizes prominently to the slit diaphragm, a specialized intercellular junction connecting foot processes of glomerular podocytes (ha2013rolesofadaptor pages 1-2, blaine2020regulationofthe pages 3-5, swiateckaurban2017endocytictraffickingat pages 1-2). At this location, CD2AP is found in lipid raft-associated junctional complexes together with nephrin, podocin, and Neph1 (blaine2020regulationofthe pages 3-5, swiateckaurban2017endocytictraffickingat pages 2-3). CD2AP also associates with endocytic vesicles and endosomal/lysosomal compartments in podocytes, where it participates in vesicle trafficking and receptor turnover (tolvanen2015lackofcd2ap pages 1-4, tian2022podocyteendocytosisin pages 1-2, swiateckaurban2017endocytictraffickingat pages 2-3).

Neurons: In the central nervous system, CD2AP protein is broadly expressed in adult mouse brain, including cortical and hippocampal neurons, where it is detected at pre-synaptic terminals (mehrabipour2023asystematiccompilation pages 1-2). CD2AP mRNA and protein are particularly enriched in TrkA-expressing cholinergic neurons of the adult basal forebrain, where the protein co-localizes with RAB5-decorated endosomes in neuronal soma (fitzsimons2024cd2apiscoexpressed pages 1-3). This localization suggests a role in retrograde trophic signaling in NGF-responsive CNS cholinergic neurons (fitzsimons2024cd2apiscoexpressed pages 1-3).

Immune Cells: Immunofluorescence revealed co-localization of CD2AP with MYO1F and the CASS group of proteins at actin-rich podosomes and phagocytic cups in macrophages and microglia (arden2024themyo1finteractome pages 1-3, arden2024themyo1finteractome pages 3-6). CD2AP is also expressed in migratory dendritic cell populations (fitzsimons2024cd2apiscoexpressed pages 1-3).

Biochemical and Signaling Pathways

1. Slit Diaphragm-Actin Cytoskeleton Coupling

CD2AP plays a critical structural and signaling role at the podocyte slit diaphragm by linking transmembrane proteins to the actin cytoskeleton (ha2013rolesofadaptor pages 1-2, blaine2020regulationofthe pages 3-5, blaine2020regulationofthe pages 1-3). CD2AP functions as an adapter protein that anchors slit diaphragm proteins (nephrin, podocin) to actin filaments of podocyte foot processes (agarwal2021renalcellmarkers pages 1-2). The nephrin-podocin-CD2AP complex provides a direct link between the signal receptor nephrin and the foot process actin cytoskeleton, as CD2AP can interact directly with F-actin as well as with cortactin and synaptopodin (blaine2020regulationofthe pages 3-5, blaine2020regulationofthe pages 1-3).

CD2AP interacts with the C-terminus of podocin and helps stabilize the nephrin-podocin complex at lipid rafts within the slit diaphragm membranes (blaine2020regulationofthe pages 3-5, swiateckaurban2017endocytictraffickingat pages 2-3). This complex is essential for maintaining foot process architecture and glomerular filtration barrier integrity (ha2013rolesofadaptor pages 1-2, yu2018proteinurickidneydiseases pages 1-2). Genetic deletion or loss of CD2AP function results in foot process effacement, defective slit diaphragm formation, and proteinuria, ultimately leading to renal failure in mice (tolvanen2015lackofcd2ap pages 1-4, blaine2020regulationofthe pages 1-3).

2. Endocytic Trafficking and Vesicle Sorting

CD2AP participates in multiple endocytic pathways, including clathrin-mediated endocytosis and clathrin-independent mechanisms (tolvanen2015lackofcd2ap pages 1-4, tian2022podocyteendocytosisin pages 1-2, swiateckaurban2017endocytictraffickingat pages 2-3). CD2AP co-localizes with COPI vesicles and clathrin and has been shown to link clathrin to the actin cytoskeleton (tolvanen2015lackofcd2ap pages 1-4). CD2AP forms a complex with the clathrin adaptor GGA2, which sorts Glut4 to Glut4 storage vesicles (GSVs) in podocytes (tolvanen2015lackofcd2ap pages 1-4).

In the absence of CD2AP, clathrin recycling back to trans-Golgi membranes from the vesicular fraction containing GSVs is defective, leading to reduced insulin-stimulated trafficking of GSVs and attenuated glucose uptake (tolvanen2015lackofcd2ap pages 1-4). CD2AP also co-fractionates with Glut4, IRAP, and sortilin, constituents of Glut4 storage vesicles, and regulates insulin-dependent glucose transporter 4 (Glut4) trafficking (tolvanen2015lackofcd2ap pages 1-4).

CD2AP is present in specific late endosomal compartments in podocytes and is involved in endosomal sorting and/or trafficking by regulating the assembly of actin on vesicles (tolvanen2015lackofcd2ap pages 1-4). The protein associates with the active form of small GTPase Rab4 and Rab5, both involved in endocytic processes (tolvanen2015lackofcd2ap pages 1-4, fitzsimons2024cd2apiscoexpressed pages 1-3).

3. Neuronal Trophic Signaling

In neurons, CD2AP functions as a docking-scaffold/adaptor protein coordinator of nerve growth factor (NGF) trophic signaling and RAB5-mediated endocytosis (fitzsimons2024cd2apiscoexpressed pages 1-3). Known upstream binding-partners include Tropomyosin receptor kinase-A (TrkA), activated by NGF, while downstream effector binding-partners include the PI3K regulatory subunit p85, p21ras, and Akt (fitzsimons2024cd2apiscoexpressed pages 1-3).

NGF stimulates CD2AP binding to TrkA and the PI3-kinase effector (p85) to upregulate the PI3K/AKT pathway, functioning as a positive coordinator of NGF-stimulated axon growth and branching (fitzsimons2024cd2apiscoexpressed pages 1-3). CD2AP scaffolding interactions regulate Rab5-mediated endocytosis, which is critical for retrograde trophic signaling through endosomal transport of internalized ligand-receptor complexes towards downstream effectors located in the cell body (fitzsimons2024cd2apiscoexpressed pages 1-3).

Recent studies demonstrate that deletion of Cd2ap altered dendritic branching and spine density, impaired ubiquitin-proteasome system activity, and resulted in increased paired-pulse facilitation at hippocampal Schaffer-collateral synapses, consistent with a haploinsufficient requirement for pre-synaptic release (mehrabipour2023asystematiccompilation pages 1-2). These findings reveal conserved, dose-sensitive requirements for CD2AP in the maintenance of neuronal structure and function, including synaptic homeostasis and plasticity (mehrabipour2023asystematiccompilation pages 1-2).

4. Podosomes and Phagocytosis

CD2AP, identified as a novel adaptor protein in podosomes and phagosomes, co-localizes with MYO1F at actin-rich podosomes and phagocytic cups in macrophages and microglia (arden2024themyo1finteractome pages 1-3, arden2024themyo1finteractome pages 3-6). Functional assays demonstrated that MYO1F recruitment to the phagocytic cup requires intact SH3 domains, which interact with the CASS group of adaptor proteins including CD2AP (arden2024themyo1finteractome pages 1-3). This work offers new insights into MYO1F function in disease-associated microglia during neurodegeneration, as CD2AP is an Alzheimer's disease (AD) risk gene upregulated in microglia of individuals with AD (arden2024themyo1finteractome pages 1-3).

5. Additional Signaling Pathways

CD2AP has been reported to interact with TRIM5, an NF-κB modulator, in glioblastoma cells (zhang2024cd2appromotesthe pages 1-2). CD2AP overexpression increased TRIM5 levels and NF-κB activity, while CD2AP knockdown had the opposite effects (zhang2024cd2appromotesthe pages 1-2). This CD2AP-TRIM5-NF-κB axis promotes glioblastoma progression through activating NF-κB signaling (zhang2024cd2appromotesthe pages 1-2).

In cultured podocytes, OCRL (an inositol 5-phosphatase) associated with the linker protein IPIP27A and CD2AP, a protein important for maintenance of the podocyte slit diaphragm (preston2020arolefor pages 1-2). CD2AP is also important in the regulation of endocytic trafficking, which requires endosomal trafficking and actin polymerization (preston2020arolefor pages 1-2).

Recent Developments and Disease Relevance (2023-2024)

Alzheimer's Disease: Genome-wide association studies (GWAS) with multiple human populations have identified single nucleotide variants of the CD2AP gene locus associated with Alzheimer's Disease (AD) risk (fitzsimons2024cd2apiscoexpressed pages 1-3, arden2024themyo1finteractome pages 1-3, mehrabipour2023asystematiccompilation pages 1-2). CD2AP is robustly expressed in non-neuronal cells and neurovasculature in the adult CNS, with restricted neuronal expression enriched in cholinergic neurons of the basal forebrain that project to the hippocampus and cortex and are required for learning and memory (fitzsimons2024cd2apiscoexpressed pages 1-3). Basal forebrain cholinergic neurons are critical for brain health during aging, and disruption of RAB5-mediated endocytosis in these neurons is central to AD pathogenesis (fitzsimons2024cd2apiscoexpressed pages 1-3).

A 2024 study demonstrated that CD2AP is a dose-sensitive determinant of synaptic structure and plasticity (mehrabipour2023asystematiccompilation pages 1-2). Cd2ap heterozygous mice demonstrated subtle impairments in discrimination learning, and based on unbiased proteomics, partial or complete loss of Cd2ap triggered perturbation of proteins with roles in protein folding, lipid metabolism, proteostasis, and synaptic function (mehrabipour2023asystematiccompilation pages 1-2).

Immune Function: CD2AP was identified in 2024 as a novel adaptor protein in podosomes and during phagocytosis, offering new insights into its function in disease-associated microglia during neurodegeneration (arden2024themyo1finteractome pages 1-3). Interestingly, CD2AP is an AD risk gene upregulated in patient microglia implicated in phagocytic responses to amyloid-β (arden2024themyo1finteractome pages 1-3).

Evidence Quality and Experimental Approaches

The functional characterization of CD2AP has employed diverse experimental approaches across multiple model systems:

Genetic models: CD2AP knockout mice die at 6 weeks due to renal failure with defective slit diaphragm formation (tolvanen2015lackofcd2ap pages 1-4, blaine2020regulationofthe pages 1-3). Conditional Cd2ap knockout and haploinsufficient mouse models have revealed dose-sensitive requirements for neuronal function (mehrabipour2023asystematiccompilation pages 1-2).
Structural studies: Structural modeling and mutagenesis confirmed multivalent proline-rich motif interactions between partner proteins and CD2AP SH3 domains (arden2024themyo1finteractome pages 1-3, mehrabipour2023asystematiccompilation pages 1-2).
Proximity labeling proteomics: In situ proximity labeling using BioID in human myeloid cells defined the MYO1F interactome and identified the SH3-domain-dependent CASS adaptor module (arden2024themyo1finteractome pages 1-3, arden2024themyo1finteractome pages 3-6).
Cell biology: Immunofluorescence, live cell imaging, subcellular fractionation, and co-immunoprecipitation studies have mapped CD2AP localization and binding partners across multiple cell types (arden2024themyo1finteractome pages 1-3, tolvanen2015lackofcd2ap pages 1-4, fitzsimons2024cd2apiscoexpressed pages 1-3, preston2020arolefor pages 1-2).
Functional assays: Studies have assessed glucose uptake, vesicle trafficking, synaptic transmission, phagocytosis, and podocyte foot process dynamics to define CD2AP functional roles (tolvanen2015lackofcd2ap pages 1-4, mehrabipour2023asystematiccompilation pages 1-2, arden2024themyo1finteractome pages 1-3).

Summary

CD2AP is a multifunctional scaffolding/adapter protein with three consecutive SH3 domains that mediate specific protein-protein interactions with diverse partners across multiple cell types. The primary molecular function of CD2AP is to link membrane receptors and junctional proteins to the actin cytoskeleton while coordinating endocytic trafficking and signaling pathways. In podocytes, CD2AP is essential for maintaining the slit diaphragm-actin connection that preserves glomerular filtration barrier integrity. In neurons, CD2AP coordinates trophic signaling and retrograde transport critical for synaptic function and neuronal maintenance. In immune cells, CD2AP participates in podosome and phagocytic cup dynamics. The protein's involvement in endocytosis, actin regulation, and signaling integration positions CD2AP as a critical node in cellular homeostasis, with implications for kidney disease, neurodegeneration, and immune function.

References

(mehrabipour2023asystematiccompilation pages 1-2): Mehrnaz Mehrabipour, Neda S. Kazemein Jasemi, Radovan Dvorsky, and Mohammad R. Ahmadian. A systematic compilation of human sh3 domains: a versatile superfamily in cellular signaling. Cells, 12:2054, Aug 2023. URL: https://doi.org/10.3390/cells12162054, doi:10.3390/cells12162054. This article has 50 citations.
(zhang2024cd2appromotesthe pages 1-2): Liang Zhang, Jiawei He, Wentao Zhao, Yuhang Zhou, Jin Li, Shaobo Li, Wenpeng Zhao, Lingliang Zhang, Ziqian Tang, Guowei Tan, Sifang Chen, Bingchang Zhang, Yun-wu Zhang, and Zhanxiang Wang. Cd2ap promotes the progression of glioblastoma multiforme via trim5-mediated nf-kb signaling. Cell Death & Disease, Oct 2024. URL: https://doi.org/10.1038/s41419-024-07094-7, doi:10.1038/s41419-024-07094-7. This article has 21 citations and is from a peer-reviewed journal.
(arden2024themyo1finteractome pages 1-3): Susan D. Arden, Eva Pennink, András Lakatos, Gillian M. Griffiths, Anna H. Lippert, and Folma Buss. The myo1f interactome reveals asap1, cd2ap and sh3kbp1 as novel adaptor proteins in podosomes and phagosomes. Journal of Cell Science, Dec 2024. URL: https://doi.org/10.1242/jcs.264357, doi:10.1242/jcs.264357. This article has 1 citations and is from a domain leading peer-reviewed journal.
(fitzsimons2024cd2apiscoexpressed pages 1-3): Lindsey Avery Fitzsimons, Mohammad Atif-Sheikh, Jayden Lovely, Madison Mueth, Makaela Rice, Kevin Kotredes, Gareth Howell, and Benjamin J Harrison. Cd2ap is co-expressed with tropomyosin-related kinase a and ras-related protein rab-5a in cholinergic neurons of the murine basal forebrain. bioRxiv, Jul 2024. URL: https://doi.org/10.1101/2024.07.24.604961, doi:10.1101/2024.07.24.604961. This article has 1 citations.
(ha2013rolesofadaptor pages 1-2): Tae-Sun Ha. Roles of adaptor proteins in podocyte biology. World journal of nephrology, 2 1:1-10, Feb 2013. URL: https://doi.org/10.5527/wjn.v2.i1.1, doi:10.5527/wjn.v2.i1.1. This article has 61 citations.
(arden2024themyo1finteractome pages 3-6): Susan D. Arden, Eva Pennink, András Lakatos, Gillian M. Griffiths, Anna H. Lippert, and Folma Buss. The myo1f interactome reveals asap1, cd2ap and sh3kbp1 as novel adaptor proteins in podosomes and phagosomes. Journal of Cell Science, Dec 2024. URL: https://doi.org/10.1242/jcs.264357, doi:10.1242/jcs.264357. This article has 1 citations and is from a domain leading peer-reviewed journal.
(blaine2020regulationofthe pages 3-5): Judith Blaine and James Dylewski. Regulation of the actin cytoskeleton in podocytes. Cells, 9:1700, Jul 2020. URL: https://doi.org/10.3390/cells9071700, doi:10.3390/cells9071700. This article has 180 citations.
(swiateckaurban2017endocytictraffickingat pages 1-2): Agnieszka Swiatecka-Urban. Endocytic trafficking at the mature podocyte slit diaphragm. Frontiers in Pediatrics, Feb 2017. URL: https://doi.org/10.3389/fped.2017.00032, doi:10.3389/fped.2017.00032. This article has 35 citations.
(tolvanen2015lackofcd2ap pages 1-4): Tuomas A. Tolvanen, Surjya Narayan Dash, Zydrune Polianskyte-Prause, Vincent Dumont, and Sanna Lehtonen. Lack of cd2ap disrupts glut4 trafficking and attenuates glucose uptake in podocytes. Journal of Cell Science, 128:4588-4600, Dec 2015. URL: https://doi.org/10.1242/jcs.175075, doi:10.1242/jcs.175075. This article has 21 citations and is from a domain leading peer-reviewed journal.
(swiateckaurban2017endocytictraffickingat pages 2-3): Agnieszka Swiatecka-Urban. Endocytic trafficking at the mature podocyte slit diaphragm. Frontiers in Pediatrics, Feb 2017. URL: https://doi.org/10.3389/fped.2017.00032, doi:10.3389/fped.2017.00032. This article has 35 citations.
(tian2022podocyteendocytosisin pages 1-2): Xuefei Tian, Patricia Bunda, and Shuta Ishibe. Podocyte endocytosis in regulating the glomerular filtration barrier. Frontiers in Medicine, Feb 2022. URL: https://doi.org/10.3389/fmed.2022.801837, doi:10.3389/fmed.2022.801837. This article has 32 citations.
(blaine2020regulationofthe pages 1-3): Judith Blaine and James Dylewski. Regulation of the actin cytoskeleton in podocytes. Cells, 9:1700, Jul 2020. URL: https://doi.org/10.3390/cells9071700, doi:10.3390/cells9071700. This article has 180 citations.
(agarwal2021renalcellmarkers pages 1-2): Shivangi Agarwal, Yashwanth R. Sudhini, Onur K. Polat, Jochen Reiser, and Mehmet M. Altintas. Renal cell markers: lighthouses for managing renal diseases. Dec 2021. URL: https://doi.org/10.1152/ajprenal.00182.2021, doi:10.1152/ajprenal.00182.2021. This article has 25 citations and is from a peer-reviewed journal.
(yu2018proteinurickidneydiseases pages 1-2): Samuel Mon-Wei Yu, Pitchaphon Nissaisorakarn, Irma Husain, and Belinda Jim. Proteinuric kidney diseases: a podocyte's slit diaphragm and cytoskeleton approach. Frontiers in Medicine, Sep 2018. URL: https://doi.org/10.3389/fmed.2018.00221, doi:10.3389/fmed.2018.00221. This article has 98 citations.
(preston2020arolefor pages 1-2): Rebecca Preston, Richard W Naylor, Graham Stewart, Agnieszka Bierzynska, Moin A Saleem, Martin Lowe, and Rachel Lennon. A role for ocrl in glomerular function and disease. Pediatric Nephrology (Berlin, Germany), 35:641-648, Dec 2020. URL: https://doi.org/10.1007/s00467-019-04317-4, doi:10.1007/s00467-019-04317-4. This article has 34 citations.

Artifacts

Citations

mehrabipour2023asystematiccompilation pages 1-2
blaine2020regulationofthe pages 3-5
agarwal2021renalcellmarkers pages 1-2
preston2020arolefor pages 1-2
ha2013rolesofadaptor pages 1-2
swiateckaurban2017endocytictraffickingat pages 1-2
swiateckaurban2017endocytictraffickingat pages 2-3
tian2022podocyteendocytosisin pages 1-2
blaine2020regulationofthe pages 1-3
yu2018proteinurickidneydiseases pages 1-2
https://doi.org/10.3390/cells12162054,
https://doi.org/10.1038/s41419-024-07094-7,
https://doi.org/10.1242/jcs.264357,
https://doi.org/10.1101/2024.07.24.604961,
https://doi.org/10.5527/wjn.v2.i1.1,
https://doi.org/10.3390/cells9071700,
https://doi.org/10.3389/fped.2017.00032,
https://doi.org/10.1242/jcs.175075,
https://doi.org/10.3389/fmed.2022.801837,
https://doi.org/10.1152/ajprenal.00182.2021,
https://doi.org/10.3389/fmed.2018.00221,
https://doi.org/10.1007/s00467-019-04317-4,

📚 Additional Documentation

Notes

(CD2AP-notes.md)

CD2AP curation notes

2026-06-19

Deep-research attempt with just deep-research-falcon human CD2AP --fallback perplexity-lite timed out after 180 seconds with no generated research artifact, so this manual review uses cached UniProt, GOA, PANTHER family, and publication evidence.
CD2AP is best treated as an SH3-domain scaffolding/adaptor protein that links membrane and junctional proteins to actin-rich cortical structures. The original CMS/CD2AP paper reports that the protein is cytoplasmic, colocalizes with F-actin and p130(Cas) in membrane ruffles and leading edges, and that ectopic expression changes actin cytoskeleton organization PMID:10339567.
Core localization annotations are cytoplasm, actin cytoskeleton/filamentous actin, ruffle, leading edge, plasma membrane/cell periphery, vesicle/endosomal compartments, and junctional structures. UniProt summarizes CD2AP as acting between membrane proteins and actin cytoskeleton, anchoring the podocyte slit diaphragm to actin, and participating in epithelial junction formation.
Homodimerization and multimeric SH3-mediated complexes are supported. The structural paper states that CD2AP/CMS family endocytic adaptors engage multiple effectors and can couple cargo trafficking to the cytoskeleton PMID:17020880, and reports that CD2 and Cbl-b peptides mediate multimerization of CMS SH3 domains PMID:17020880.
The broad protein binding annotations should not be accepted as core terms. Several are real interaction observations, but CD2AP's informative molecular role is adaptor/scaffold activity, SH3/proline-rich partner recognition, actin association, or specific complex context rather than generic protein binding.
Epithelial junction evidence is strong. A full-text JCB paper reports that SH3BP1 formed a complex with JACOP/paracingulin and CD2AP, and that both scaffold proteins were required for normal Cdc42 signaling and junction formation PMID:22891260. This supports anchoring junction, actin filament organization, and negative regulation of small GTPase signaling annotations.
CD2AP is also part of the submembrane actin/junction module through CapZ. The same paper states that CD2AP is part of the submembrane actin cytoskeleton and binds/regulates CapZ PMID:22891260.
Podocyte slit diaphragm localization is biologically central for CD2AP in vivo, even though several slit-diaphragm details in the current GOA set are electronically transferred. I accepted slit diaphragm/anchoring junction context because it is consistent with UniProt and the established renal disease association.
Neuronal axon/dendrite and synapse annotations are plausible Alzheimer/endosomal context but are not the primary evolved function of CD2AP. The RIN3 Alzheimer paper shows that RIN3 recruited BIN1 and CD2AP to early endosomes and that RIN3/CD2AP expression affected APP cleavage/trafficking in neuronal models PMID:32552912. I kept axon/dendrite/synapse context non-core rather than making it the defining function.
The tau secretion annotation from PMID:27044754 is experimental but the cached record is abstract-only and the abstract names FRMD4A rather than CD2AP. Following the project rule not to overrule curators from incomplete evidence, I marked this annotation UNDECIDED rather than removing it PMID:27044754.
High-throughput cadhesome, exosome, AD network, and interactome annotations are useful context but not core molecular function evidence. Cadherin binding from E-cadherin proximity proteomics is over-specific for CD2AP because the paper describes a large cadhesome proximity/interactome resource rather than direct CD2AP cadherin binding PMID:25468996.

2026-06-20 Second-Pass Review Notes

Second-pass audit confirmed the existing action calls and reference-review
coverage. No YAML changes were needed in this pass.

The single UNDECIDED annotation remains GO:0050714 positive regulation of
protein secretion from PMID:27044754. The cached record is abstract-only and
foregrounds FRMD4A rather than exposing the CD2AP-specific experimental result.
Because the annotation is experimental, it should remain UNDECIDED rather than
be removed without full-text or supplementary-data review.

The core function remains SH3-domain scaffold/adaptor activity linking membrane,
endocytic, junctional, and slit-diaphragm partner complexes to actin-rich
cortical structures. Alzheimer relevance should be represented through
endosomal trafficking modules involving RIN3/BIN1/CD2AP and APP/tau-related
cellular phenotypes, not as generic protein-binding function.

Falcon deep research integration (2026-06-21)

A freshly-grounded Falcon/Edison deep-research report (CD2AP-deep-research-falcon.md, ~22 cited
sources) is now available; it corroborates the existing review's core picture well — CD2AP as a
multi-SH3 scaffold/adaptor linking nephrin/podocin slit-diaphragm and junctional complexes to actin,
plus endocytic/vesicle trafficking and Alzheimer relevance — and adds no contradictions, only
context. The following Falcon-sourced citations are NOT yet independently verified against full text.

Genuinely new or refined findings beyond the current notes/review:

Explicit nephrin–podocin–CD2AP–actin axis: CD2AP scaffolds the slit-diaphragm receptor nephrin and
binds the podocin C-terminus, coupling slit-diaphragm signaling to F-actin via cortactin and
synaptopodin [Blaine & Dylewski, Cells 2020, doi:10.3390/cells9071700; Ha, World J Nephrol 2013,
doi:10.5527/wjn.v2.i1.1]. This refines the existing review, which treats slit diaphragm largely as
electronically-transferred localization rather than a named nephrin/podocin partner module.
Insulin-responsive Glut4 trafficking: CD2AP forms a complex with the clathrin adaptor GGA2 and
co-fractionates with Glut4/IRAP/sortilin; loss of CD2AP disrupts GSV/clathrin recycling and
attenuates insulin-stimulated glucose uptake in podocytes [Tolvanen et al., J Cell Sci 2015,
doi:10.1242/jcs.175075]. This is a NEW functional module not represented in the existing review.
Neuronal NGF/TrkA trophic-signaling scaffold: CD2AP is enriched in TrkA+ basal-forebrain
cholinergic neurons, co-localizes with Rab5 endosomes, and couples TrkA to PI3K-p85/Akt to support
NGF-dependent axon growth and retrograde signaling [Fitzsimons et al., bioRxiv 2024,
doi:10.1101/2024.07.24.604961 — preprint, treat cautiously]. Refines the currently generic
neuron-projection/synapse non-core annotations toward a specific NGF/Rab5 retrograde-trafficking role.
MYO1F/CASS podosome and phagocytic-cup module: proximity-labeling (BioID) in myeloid cells places
CD2AP with ASAP1, SH3BP2 and SH3KBP1/CIN85 in an SH3-dependent "CASS" adaptor group recruited to
podosomes and phagocytic cups in macrophages/microglia [Arden et al., J Cell Sci 2024,
doi:10.1242/jcs.264357]. This adds molecular partners and a phagocytosis context to the existing
KEEP_AS_NON_CORE podosome annotation (GO:0002102).
Dose-sensitive synaptic role: heterozygous Cd2ap mice show altered dendritic branching/spine
density, impaired ubiquitin-proteasome activity, increased paired-pulse facilitation, and mild
learning deficits, supporting a haploinsufficient presynaptic requirement [SH3-superfamily/synaptic
work cited as Mehrabipour et al., Cells 2023, doi:10.3390/cells12162054 — NOTE: this token is cited
by Falcon for synaptic-plasticity claims that read like a separate mouse study, so the citation
mapping should be checked against full text before reuse].
Glioblastoma CD2AP–TRIM5–NF-κB axis: CD2AP stabilizes TRIM5 and promotes NF-κB activity and GBM
progression [Zhang et al., Cell Death Dis 2024, doi:10.1038/s41419-024-07094-7]. New disease context
(oncogenic), absent from the existing review; would be non-core if curated.
OCRL/IPIP27A link: CD2AP associates with the inositol-5-phosphatase OCRL via IPIP27A in podocytes,
tying it to endosomal trafficking and actin polymerization [Preston et al., Pediatr Nephrol 2020,
doi:10.1007/s00467-019-04317-4]. Corroborates the endocytic-adaptor theme.

Discrepancies / annotations to revisit:
- No direct contradictions with the existing review or its action calls.
- The Glut4/GGA2/insulin-trafficking and NGF/TrkA/Rab5 modules suggest the existing endocytic-adaptor
core could be strengthened with a clathrin/endocytic-vesicle process term (e.g. consider whether
GO:0072583 clathrin-dependent endocytosis or GO:0006897 endocytosis better captures the
Tolvanen/Arden evidence than relying on GO:0030276 clathrin binding alone). Defer pending full-text
verification.
- The MYO1F/CASS data (Arden 2024) provide a concrete molecular basis for the GO:0002102 podosome
KEEP_AS_NON_CORE call and could be cited there if verified.
- Per project guidelines, do not promote any of these to "protein binding"; route new partner
evidence through specific adaptor/SH3/actin or process terms instead.

📄 View Raw YAML

id: Q9Y5K6
gene_symbol: CD2AP
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'CD2AP encodes CD2-associated protein, a multi-SH3-domain adaptor/scaffolding
  protein that connects membrane, endosomal, and junctional protein complexes to the
  actin cytoskeleton. It localizes to cytoplasm, actin-rich ruffles and leading edges,
  vesicle/endosomal compartments, epithelial junctions, and the podocyte slit diaphragm.
  CD2AP organizes multimeric partner complexes through SH3/proline-rich and coiled-coil
  interactions, supports actin filament organization and cell extension, contributes
  to epithelial junction formation by helping position a SH3BP1/JACOP/CapZ module
  that confines Cdc42 signaling, and participates in endocytic/receptor-trafficking
  contexts relevant to neuronal and Alzheimer disease models.'
existing_annotations:
- term:
    id: GO:0016477
    label: cell migration
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: CD2AP promotes actin-linked cell extension and migration as part of
      its cortical adaptor/scaffold function.
    action: ACCEPT
    reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that
      colocalizes with F-actin at ruffles and leading edges, alters actin 
      organization, forms multimeric partner complexes, and links membrane or 
      junctional proteins to the actin cytoskeleton.
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: CD2AP is a membrane- and junction-associated adaptor/scaffold that 
      links partner proteins to actin-rich cortical and endosomal compartments.
    action: ACCEPT
    reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that
      colocalizes with F-actin at ruffles and leading edges, alters actin 
      organization, forms multimeric partner complexes, and links membrane or 
      junctional proteins to the actin cytoskeleton.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0007015
    label: actin filament organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: CD2AP directly supports actin cytoskeleton organization and acts in
      actin-rich ruffles, cell extensions, and epithelial junction remodeling.
    action: ACCEPT
    reason: Retain as core because the original CMS/CD2AP study and later 
      junction work support CD2AP as an actin-associated scaffold that regulates
      actin arrangement, cell extensions, and junctional actin remodeling.
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0031252
    label: cell leading edge
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0001726
    label: ruffle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: part_of
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0070161
    label: anchoring junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17020880
  qualifier: enables
  review:
    summary: The cited interaction is compatible with CD2AP scaffold biology, 
      but generic protein binding is too broad for the actual molecular role.
    action: MODIFY
    reason: Generic protein binding does not capture CD2AP function; the 
      informative biology is SH3/proline-rich partner recognition, 
      adaptor/scaffold activity, actin association, or specific 
      junction/endosomal complex participation.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17474147
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17853893
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19380743
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21706016
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21822214
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22662192
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23663663
  qualifier: enables
  review:
    summary: The cited interaction is compatible with CD2AP scaffold biology, 
      but generic protein binding is too broad for the actual molecular role.
    action: MODIFY
    reason: Generic protein binding does not capture CD2AP function; the 
      informative biology is SH3/proline-rich partner recognition, 
      adaptor/scaffold activity, actin association, or specific 
      junction/endosomal complex participation.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31413325
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32552912
  qualifier: enables
  review:
    summary: The cited interaction is compatible with CD2AP scaffold biology, 
      but generic protein binding is too broad for the actual molecular role.
    action: MODIFY
    reason: Generic protein binding does not capture CD2AP function; the 
      informative biology is SH3/proline-rich partner recognition, 
      adaptor/scaffold activity, actin association, or specific 
      junction/endosomal complex participation.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:17020880
  qualifier: enables
  review:
    summary: Structural and biochemical evidence supports multimerization of 
      CD2AP/CMS SH3-domain complexes, consistent with homotypic/multimeric 
      scaffold assembly.
    action: ACCEPT
    reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that
      colocalizes with F-actin at ruffles and leading edges, alters actin 
      organization, forms multimeric partner complexes, and links membrane or 
      junctional proteins to the actin cytoskeleton.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:31413325
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0002102
    label: podosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Podosome localization is plausible for an actin-rich adhesion 
      scaffold but is not the central CD2AP function established by the 
      strongest evidence.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because podosomes are an actin-rich adhesion 
      context related to CD2AP cytoskeletal biology but are less central than 
      ruffles, junctions, slit diaphragm, and endosomal adaptor functions.
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: CD2AP is an actin-associated scaffold, and actin/actin-filament 
      binding is consistent with the original CMS/CD2AP functional evidence and 
      later CapZ-linked junction work.
    action: ACCEPT
    reason: Retain as core because the original CMS/CD2AP study and later 
      junction work support CD2AP as an actin-associated scaffold that regulates
      actin arrangement, cell extensions, and junctional actin remodeling.
- term:
    id: GO:0005641
    label: nuclear envelope lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005770
    label: late endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005884
    label: actin filament
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005911
    label: cell-cell junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: CD2AP/CIN85-family adaptor biology supports vesicle, late-endosome,
      TGN, and clathrin-linked trafficking annotations, with Alzheimer-context 
      evidence for RIN3/BIN1/CD2AP early-endosome recruitment.
    action: ACCEPT
    reason: Retain as core or near-core because CD2AP is an endocytic adaptor 
      family member that couples cargo trafficking to the cytoskeleton and 
      participates in early-endosomal/receptor-trafficking contexts.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0032588
    label: trans-Golgi network membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0036057
    label: slit diaphragm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0036312
    label: phosphatidylinositol 3-kinase regulatory subunit binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: CD2AP proline-rich sequences bind signaling SH3-domain partners 
      including the p85 regulatory subunit of phosphatidylinositol 3-kinase, 
      fitting its adaptor role.
    action: ACCEPT
    reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that
      colocalizes with F-actin at ruffles and leading edges, alters actin 
      organization, forms multimeric partner complexes, and links membrane or 
      junctional proteins to the actin cytoskeleton.
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0050808
    label: synapse organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0051015
    label: actin filament binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: CD2AP is an actin-associated scaffold, and actin/actin-filament 
      binding is consistent with the original CMS/CD2AP functional evidence and 
      later CapZ-linked junction work.
    action: ACCEPT
    reason: Retain as core because the original CMS/CD2AP study and later 
      junction work support CD2AP as an actin-associated scaffold that regulates
      actin arrangement, cell extensions, and junctional actin remodeling.
- term:
    id: GO:0071944
    label: cell periphery
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0070161
    label: anchoring junction
  evidence_type: EXP
  original_reference_id: PMID:22891260
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISS
  original_reference_id: PMID:32552912
  qualifier: located_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: ISS
  original_reference_id: PMID:32552912
  qualifier: located_in
  review:
    summary: Neuronal projection or synapse context is plausible in 
      Alzheimer/endosomal models but is not the primary defining activity of 
      CD2AP.
    action: KEEP_AS_NON_CORE
    reason: Keep as non-core because CD2AP has neuronal/endosomal disease-model 
      evidence, but the strongest conserved function remains SH3-mediated 
      adaptor/scaffold activity at actin-rich membrane, junction, and endosomal 
      structures.
- term:
    id: GO:0050714
    label: positive regulation of protein secretion
  evidence_type: IMP
  original_reference_id: PMID:27044754
  qualifier: involved_in
  review:
    summary: The tau-secretion paper is abstract-only in the cache and the 
      abstract foregrounds FRMD4A rather than CD2AP, so the CD2AP-specific 
      experimental basis cannot be verified here.
    action: UNDECIDED
    reason: Use UNDECIDED rather than REMOVE because this is an experimental 
      annotation and the cached abstract does not expose the CD2AP-specific 
      evidence that curators may have used from the full text.
- term:
    id: GO:0045296
    label: cadherin binding
  evidence_type: HDA
  original_reference_id: PMID:25468996
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22891260
  qualifier: enables
  review:
    summary: The cited interaction is compatible with CD2AP scaffold biology, 
      but generic protein binding is too broad for the actual molecular role.
    action: MODIFY
    reason: Generic protein binding does not capture CD2AP function; the 
      informative biology is SH3/proline-rich partner recognition, 
      adaptor/scaffold activity, actin association, or specific 
      junction/endosomal complex participation.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
- term:
    id: GO:0007015
    label: actin filament organization
  evidence_type: IMP
  original_reference_id: PMID:22891260
  qualifier: involved_in
  review:
    summary: CD2AP directly supports actin cytoskeleton organization and acts in
      actin-rich ruffles, cell extensions, and epithelial junction remodeling.
    action: ACCEPT
    reason: Retain as core because the original CMS/CD2AP study and later 
      junction work support CD2AP as an actin-associated scaffold that regulates
      actin arrangement, cell extensions, and junctional actin remodeling.
- term:
    id: GO:0051058
    label: negative regulation of small GTPase mediated signal transduction
  evidence_type: IMP
  original_reference_id: PMID:22891260
  qualifier: involved_in
  review:
    summary: CD2AP is part of a SH3BP1/JACOP/CapZ junctional scaffold required 
      for normal Cdc42 signaling, actin remodeling, and epithelial junction 
      formation.
    action: ACCEPT
    reason: Retain as core because full-text evidence shows CD2AP in a 
      junctional scaffold with SH3BP1/JACOP and CapZ; CD2AP depletion impaired 
      junctional SH3BP1 targeting, Cdc42 control, and junction formation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18641129
  qualifier: enables
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: This annotation comes from generic interaction, high-throughput, 
      dataset, or low-specificity localization evidence and does not define 
      CD2AP core molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mark as over-annotated because this high-throughput or generic 
      interaction/localization evidence is less informative than CD2AP adaptor, 
      actin-cytoskeleton, endosomal, and junctional terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10339567
  qualifier: enables
  review:
    summary: The cited interaction is compatible with CD2AP scaffold biology, 
      but generic protein binding is too broad for the actual molecular role.
    action: MODIFY
    reason: Generic protein binding does not capture CD2AP function; the 
      informative biology is SH3/proline-rich partner recognition, 
      adaptor/scaffold activity, actin association, or specific 
      junction/endosomal complex participation.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    - id: GO:0051015
      label: actin filament binding
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: IPI
  original_reference_id: PMID:10339567
  qualifier: enables
  review:
    summary: CD2AP has proline-rich regions that bind SH3-domain-containing 
      partners, supporting its scaffold/adaptor function.
    action: ACCEPT
    reason: CD2AP/CMS is characterized as an SH3-domain scaffolding adaptor that
      colocalizes with F-actin at ruffles and leading edges, alters actin 
      organization, forms multimeric partner complexes, and links membrane or 
      junctional proteins to the actin cytoskeleton.
- term:
    id: GO:0001726
    label: ruffle
  evidence_type: IDA
  original_reference_id: PMID:10339567
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0031941
    label: filamentous actin
  evidence_type: IDA
  original_reference_id: PMID:10339567
  qualifier: part_of
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: NAS
  original_reference_id: PMID:10339567
  qualifier: involved_in
  review:
    summary: The 1999 paper supports CD2AP as a scaffold/adaptor involved in 
      cytoskeletal rearrangement, but broad signal transduction is not specific 
      enough.
    action: MODIFY
    reason: Replace broad signal transduction with the more specific adaptor and
      actin-organization functions supported by the same study.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    - id: GO:0007015
      label: actin filament organization
- term:
    id: GO:0005200
    label: structural constituent of cytoskeleton
  evidence_type: TAS
  original_reference_id: PMID:10339567
  qualifier: enables
  review:
    summary: CD2AP is an actin-associated scaffold, but structural constituent 
      of cytoskeleton overstates the evidence compared with 
      adaptor/actin-binding function.
    action: MODIFY
    reason: Replace structural constituent of cytoskeleton with CD2AP adaptor 
      activity and actin filament binding, which better describe the evidence.
    proposed_replacement_terms:
    - id: GO:0030674
      label: protein-macromolecule adaptor activity
    - id: GO:0051015
      label: actin filament binding
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:10339567
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0006930
    label: substrate-dependent cell migration, cell extension
  evidence_type: TAS
  original_reference_id: PMID:10339567
  qualifier: involved_in
  review:
    summary: CD2AP directly supports actin cytoskeleton organization and acts in
      actin-rich ruffles, cell extensions, and epithelial junction remodeling.
    action: ACCEPT
    reason: Retain as core because the original CMS/CD2AP study and later 
      junction work support CD2AP as an actin-associated scaffold that regulates
      actin arrangement, cell extensions, and junctional actin remodeling.
- term:
    id: GO:0015629
    label: actin cytoskeleton
  evidence_type: TAS
  original_reference_id: PMID:10339567
  qualifier: located_in
  review:
    summary: This location matches CD2AP localization to cytoplasm, cortical 
      actin structures, ruffles/leading edges, vesicles/endosomal compartments, 
      plasma membrane, and junctional/slit-diaphragm sites.
    action: ACCEPT
    reason: Retain as core because CD2AP acts at actin-rich membrane and 
      junction compartments, including ruffles, leading edges, 
      cell-cell/anchoring junctions, podocyte slit diaphragm context, and 
      vesicle/endosomal sites.
- term:
    id: GO:0065003
    label: protein-containing complex assembly
  evidence_type: TAS
  original_reference_id: PMID:10339567
  qualifier: involved_in
  review:
    summary: CD2AP directly supports actin cytoskeleton organization and acts in
      actin-rich ruffles, cell extensions, and epithelial junction remodeling.
    action: ACCEPT
    reason: Retain as core because the original CMS/CD2AP study and later 
      junction work support CD2AP as an actin-associated scaffold that regulates
      actin arrangement, cell extensions, and junctional actin remodeling.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data
    to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning 
    models
  findings: []
- id: PMID:10339567
  title: 'CMS: an adapter molecule involved in cytoskeletal rearrangements.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary CMS/CD2AP paper supporting adaptor/scaffold, actin 
      cytoskeleton, ruffle/leading-edge, homodimerization, and cell-extension 
      annotations.
- id: PMID:17020880
  title: Atypical polyproline recognition by the CMS N-terminal Src homology 3 
    domain.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Structural/biochemical evidence for CD2AP/CMS SH3-mediated 
      partner recognition and multimeric adaptor complexes.
- id: PMID:17474147
  title: Systematic identification of SH3 domain-mediated human protein-protein 
    interactions by peptide array target screening.
  findings: []
- id: PMID:17853893
  title: Human ESCRT and ALIX proteins interact with proteins of the midbody and
    function in cytokinesis.
  findings: []
- id: PMID:18641129
  title: Differential requirements for Alix and ESCRT-III in cytokinesis and 
    HIV-1 release.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19380743
  title: Charting the molecular network of the drug target Bcr-Abl.
  findings: []
- id: PMID:21706016
  title: Selected reaction monitoring mass spectrometry reveals the dynamics of 
    signaling through the GRB2 adaptor.
  findings: []
- id: PMID:21822214
  title: The B-cell antigen receptor signals through a preformed transducer 
    module of SLP65 and CIN85.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human
    liver.
  findings: []
- id: PMID:22662192
  title: IQGAP1 interacts with components of the slit diaphragm complex in 
    podocytes and is involved in podocyte migration and permeability in vitro.
  findings: []
- id: PMID:22891260
  title: Epithelial junction formation requires confinement of Cdc42 activity by
    a novel SH3BP1 complex.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text primary evidence for CD2AP in a junctional 
      SH3BP1/JACOP/CapZ scaffold required for Cdc42 control and epithelial 
      junction formation.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed 
    prostatic secretions in urine.
  findings: []
- id: PMID:23663663
  title: Multimeric and differential binding of CIN85/CD2AP with two atypical 
    proline-rich sequences from CD2 and Cbl-b*.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Biophysical evidence for multimeric CD2AP/CIN85 SH3 
      interactions with CD2 and Cbl-b proline-rich regions.
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture 
    of cellular protein homeostasis pathways.
  findings: []
- id: PMID:25468996
  title: E-cadherin interactome complexity and robustness resolved by 
    quantitative proteomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: E-cadherin proximity proteomics resource; useful junction 
      context but insufficient for core direct cadherin-binding function.
- id: PMID:27044754
  title: FRMD4A-cytohesin signaling modulates the cellular release of tau.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Cached record is abstract-only and does not expose 
      CD2AP-specific tau-secretion evidence; related GO annotation left 
      UNDECIDED.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and 
    disease networks.
  findings: []
- id: PMID:31413325
  title: HENA, heterogeneous network-based data set for Alzheimer's disease.
  findings: []
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells 
    expressing transforming levels of KRAS(G13D).
  findings: []
- id: PMID:32552912
  title: Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's 
    disease.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Alzheimer/endosomal study supporting RIN3 recruitment of 
      CD2AP/BIN1 to early endosomes and APP trafficking/processing context.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the 
    human interactome.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional
    genomics.
  findings: []
- id: file:human/CD2AP/CD2AP-deep-research-falcon.md
  title: Falcon deep research report for CD2AP
  findings:
  - statement: Falcon deep research corroborates the review's core picture of CD2AP
      as a multi-SH3 scaffold/adaptor that links membrane and slit-diaphragm
      partner proteins to the actin cytoskeleton.
    supporting_text: CD2AP functions primarily as a scaffolding/adapter protein
      that coordinates protein-protein interactions through its structural domains
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: Falcon/Edison deep-research synthesis; corroborates the existing
      scaffold/adaptor and slit-diaphragm-to-actin picture. Underlying Falcon
      citations not yet independently verified against full text.
core_functions:
- molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  description: CD2AP functions as a multivalent SH3-domain scaffold/adaptor that
    links membrane-associated partner proteins and signaling complexes to 
    actin-rich cortical structures, supporting actin organization, cell 
    extension, and partner-complex assembly.
  directly_involved_in:
  - id: GO:0007015
    label: actin filament organization
  - id: GO:0016477
    label: cell migration
  - id: GO:0006930
    label: substrate-dependent cell migration, cell extension
  - id: GO:0065003
    label: protein-containing complex assembly
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0015629
    label: actin cytoskeleton
  - id: GO:0001726
    label: ruffle
  - id: GO:0031252
    label: cell leading edge
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:10339567
    supporting_text: functions as a scaffolding molecule with a specialized role
      in regulation of the actin cytoskeleton
  - reference_id: PMID:10339567
    supporting_text: colocalizes with F-actin and p130(Cas) to membrane ruffles 
      and leading edges of cells
  - reference_id: PMID:17020880
    supporting_text: can mediate multimerization of N-terminal CMS SH3 domains
- molecular_function:
    id: GO:0051015
    label: actin filament binding
  description: CD2AP associates with F-actin-rich cortical and junctional 
    structures and helps coordinate actin remodeling through scaffolded 
    complexes that include CapZ and SH3BP1/JACOP.
  directly_involved_in:
  - id: GO:0007015
    label: actin filament organization
  - id: GO:0051058
    label: negative regulation of small GTPase mediated signal transduction
  locations:
  - id: GO:0015629
    label: actin cytoskeleton
  - id: GO:0005884
    label: actin filament
  - id: GO:0005911
    label: cell-cell junction
  - id: GO:0070161
    label: anchoring junction
  - id: GO:0036057
    label: slit diaphragm
  supported_by:
  - reference_id: PMID:22891260
    supporting_text: both were required for normal Cdc42 signaling and junction
      formation
  - reference_id: PMID:22891260
    supporting_text: submembrane actin cytoskeleton and binds and regulates CapZ
  - reference_id: PMID:10339567
    supporting_text: Ectopic expression of CMS in COS-7 cells resulted in
      alteration in arrangement of the actin cytoskeleton
  - reference_id: file:human/CD2AP/CD2AP-deep-research-falcon.md
    supporting_text: CD2AP functions as an adapter protein that anchors slit
      diaphragm proteins (nephrin, podocin) to actin filaments of podocyte foot
      processes
- molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  description: CD2AP also acts in endocytic and receptor-trafficking modules, 
    coupling cargo and signaling complexes to cytoskeletal machinery at 
    vesicles, endosomes, and trans-Golgi network-associated membranes.
  directly_involved_in:
  - id: GO:0065003
    label: protein-containing complex assembly
  locations:
  - id: GO:0031982
    label: vesicle
  - id: GO:0005770
    label: late endosome
  - id: GO:0032588
    label: trans-Golgi network membrane
  supported_by:
  - reference_id: PMID:17020880
    supporting_text: trafficking with the cytoskeleton
  - reference_id: PMID:17020880
    supporting_text: required for an efficient internalization of cell surface 
      receptors
  - reference_id: PMID:32552912
    supporting_text: RIN3 recruited BIN1(bridging integrator 1) and CD2AP (CD2 
      associated protein)
proposed_new_terms: []
suggested_questions:
- question: Should CD2AP endocytic adaptor biology be curated with a specific 
    clathrin/endocytosis adaptor term rather than repeated generic protein 
    binding annotations?
  experts:
  - GO molecular-function curators
  - Endocytosis and adaptor-protein experts
- question: Which neuronal axon, dendrite, and synapse annotations are directly 
    supported for CD2AP itself versus inherited from Alzheimer/RIN3 endosomal 
    disease-model context?
  experts:
  - Neuronal endosomal trafficking experts
  - Alzheimer disease genetics curators
- question: Should podocyte slit-diaphragm CD2AP biology include a more specific
    process annotation for slit diaphragm organization or maintenance?
  experts:
  - Podocyte biology experts
  - GO cellular-component/process curators
suggested_experiments:
- description: Edit or rescue CD2AP SH3 domains, proline-rich region, 
    coiled-coil region, and actin-associated C-terminal region in epithelial 
    cells and podocyte models, then measure partner recruitment, junction 
    assembly, slit-diaphragm marker organization, Cdc42 spatial activity, and 
    actin dynamics.
  hypothesis: CD2AP scaffold domains separably control partner multimerization, 
    actin association, and junction/slit-diaphragm organization.
  experiment_type: domain-resolved junction and actin scaffold rescue assay
- description: Perturb CD2AP, RIN3, and BIN1 singly and in combination in 
    primary neurons or induced neuronal cultures, then quantify APP/BACE1 
    trafficking, early-endosome recruitment, axonal transport, APP C-terminal 
    fragments, and tau secretion.
  hypothesis: The Alzheimer-associated RIN3-BIN1-CD2AP module affects APP and 
    tau-related phenotypes through endosomal trafficking rather than through a 
    generic protein-binding function.
  experiment_type: neuronal endosomal trafficking and APP-processing assay

CD2AP

Gene Description

Existing Annotations Review

Core Functions

CD2AP functions as a multivalent SH3-domain scaffold/adaptor that links membrane-associated partner proteins and signaling complexes to actin-rich cortical structures, supporting actin organization, cell extension, and partner-complex assembly.

CD2AP associates with F-actin-rich cortical and junctional structures and helps coordinate actin remodeling through scaffolded complexes that include CapZ and SH3BP1/JACOP.

CD2AP also acts in endocytic and receptor-trafficking modules, coupling cargo and signaling complexes to cytoskeletal machinery at vesicles, endosomes, and trans-Golgi network-associated membranes.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: CD2AP (CD2-Associated Protein)

Gene and Protein Identity

Primary Molecular Function and Structure

Subcellular Localization

Biochemical and Signaling Pathways

Recent Developments and Disease Relevance (2023-2024)

Evidence Quality and Experimental Approaches

Summary

Artifacts

Citations

📚 Additional Documentation

Notes

CD2AP curation notes

2026-06-19

2026-06-20 Second-Pass Review Notes

Falcon deep research integration (2026-06-21)

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