Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0051015 actin filament binding	IBA GO_REF:0000033	ACCEPT	Summary: TPM3 is a well-established actin-binding protein. UniProt states "Binds to actin filaments in muscle and non-muscle cells" [UniProt P06753]. Both the muscle isoform (285 AA) and cytoskeletal TM30nm isoform (248 AA) bind actin filaments, though with different properties. PMID:3018581 confirms tissue-specific expression with "a 2.5-kilobase (kb) mRNA encoding a 248-amino-acid tropomyosin in human fibroblasts" (cytoskeletal) and "a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle." This is a core molecular function shared across all isoforms. Reason: Actin filament binding is a fundamental molecular function of all tropomyosin isoforms. The IBA annotation is well-supported by the phylogenetic conservation of this function across the tropomyosin family and direct experimental evidence from multiple studies. This represents a core function of TPM3. Supporting Evidence: PMID:3018581 a 2.5-kilobase (kb) mRNA encoding a 248-amino-acid tropomyosin in human fibroblasts and a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle file:human/TPM3/TPM3-uniprot.txt Binds to actin filaments in muscle and non-muscle cells file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle.
GO:0007015 actin filament organization	IBA GO_REF:0000033	ACCEPT	Summary: TPM3 contributes to actin filament organization in both muscle and non-muscle contexts. UniProt states that in non-muscle cells TPM3 is implicated in stabilizing cytoskeleton actin filaments, while the muscle isoform contributes to thin-filament regulation. This process annotation appropriately captures the conserved role of tropomyosins in organizing actin filament architecture. Reason: Actin filament organization is a well-supported biological process for TPM3. The IBA annotation reflects the conserved role of tropomyosins in organizing and stabilizing actin filament structures. This applies to both muscle (thin filament organization) and non-muscle (cytoskeletal) isoforms, representing a core function of the gene. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle.
GO:0005884 actin filament	IBA GO_REF:0000033	ACCEPT	Summary: TPM3 localizes to actin filaments as an integral component. Tropomyosins are coiled-coil proteins that bind along the length of actin filaments. UniProt confirms "Binds to actin filaments in muscle and non-muscle cells" [UniProt P06753]. In muscle, TPM3 is part of the thin filament; in non-muscle cells, it decorates cytoskeletal actin filaments. This localization is fundamental to tropomyosin function. Reason: Actin filament is the correct cellular component for TPM3 localization. This is a core structural feature of tropomyosins - they bind along the entire length of actin filaments as coiled-coil dimers. The IBA annotation is phylogenetically well-supported across the tropomyosin family. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Binds to actin filaments in muscle and non-muscle cells file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle.
GO:0006936 muscle contraction	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Muscle contraction is a function specific to TPM3 Isoform 1 (skeletal muscle isoform, 285 AA). UniProt states TPM3 "Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction" [UniProt P06753]. The cytoskeletal isoforms (TM30nm) do not participate in muscle contraction. TPM3 Isoform 1 is expressed in slow-twitch (type I) skeletal muscle fibers. Disease mutations causing CMYO4A demonstrate the importance of this function. Reason: Muscle contraction is valid for the skeletal muscle isoform (Isoform 1) but not for cytoskeletal isoforms (Isoform 2/TM30nm and others). Since this annotation applies to only a subset of isoforms expressed in specific tissues, it should be marked as non-core. The core function of TPM3 across all isoforms is actin filament binding and organization, while muscle contraction is tissue/isoform-specific. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction PMID:3018581 a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle.
GO:0003779 actin binding	IEA GO_REF:0000043	ACCEPT	Summary: This IEA annotation for "actin binding" is derived from UniProt keyword mapping. While technically correct, it is less specific than the IBA annotation for GO:0051015 "actin filament binding" which better captures the mechanism by which TPM3 binds actin (along the filament, not to monomeric actin). Reason: While GO:0051015 "actin filament binding" is more specific and preferred, this broader "actin binding" annotation is not incorrect. TPM3 does bind actin (specifically filamentous actin). The IEA provides complementary support to the more specific IBA annotation. Both can coexist as the more specific term is appropriately annotated via IBA. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Binds to actin filaments in muscle and non-muscle cells
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: This IEA annotation for cytoskeleton localization is derived from UniProt subcellular location mapping. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location [UniProt P06753]. While correct, more specific terms like "actin filament" (GO:0005884) or "stress fiber" (GO:0001725) better describe the actual localization of TPM3. Reason: The cytoskeleton annotation is a valid but general cellular component term. TPM3 is indeed a cytoskeletal protein, associating with actin filaments in both muscle and non-muscle cells. The more specific IBA annotation to "actin filament" (GO:0005884) provides better granularity, but this broader term is not incorrect. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0005862 muscle thin filament tropomyosin	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: This IEA annotation from ARBA machine learning correctly identifies TPM3 as a component of muscle thin filament tropomyosin. However, this applies specifically to Isoform 1 (skeletal muscle isoform). The cytoskeletal isoforms (TM30nm/Isoform 2) are not part of the muscle thin filament structure. PMID:3018581 and PMID:3418707 clearly describe the tissue-specific alternative splicing that produces distinct muscle and non-muscle isoforms. Reason: This annotation is accurate for the muscle isoform (Isoform 1) but not for cytoskeletal isoforms. The muscle thin filament complex includes tropomyosin in association with troponin for calcium-regulated muscle contraction. Since this is isoform-specific, it represents a non-core function. The core localization applicable to all isoforms is "actin filament" (GO:0005884). Supporting Evidence: PMID:3418707 In muscle, alternative splicing of this gene results in the expression of a 1.3 kb mRNA encoding a 285 amino acid skeletal muscle alpha-tropomyosin file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle.
GO:0005515 protein binding	IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp...	MARK AS OVER ANNOTATED	Summary: This IPI annotation is from a large-scale TNF-alpha/NF-kappa B signaling pathway mapping study (PMID:14743216). The generic "protein binding" term provides limited functional information about TPM3's specific interactions. TPM3 is known to interact with specific partners including TMOD1, TNNT1, and the troponin complex in muscle [UniProt P06753]. Reason: The term "protein binding" (GO:0005515) is uninformative for GO annotation purposes. While TPM3 clearly interacts with proteins (actin, troponin components, etc.), this generic term does not capture the functional nature of those interactions. More specific molecular function terms like "actin filament binding" (GO:0051015) are already annotated. High-throughput interactome studies often identify many interactions without functional validation. Supporting Evidence: PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:16189514 (large-scale human protein-protein interaction network mapping) uses the generic "protein binding" term. This is a high-throughput study that identified many interactions without specific functional characterization. Reason: The term "protein binding" is uninformative and considered a bad practice for GO annotation. TPM3's specific protein interactions (actin filaments, troponin complex, TMOD1, TNNT1) are better captured by more specific terms. Large-scale interactome data should ideally be used to generate more specific interaction annotations. Supporting Evidence: PMID:16189514 Towards a proteome-scale map of the human protein-protein interaction network
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:17353931 (large-scale mapping of human protein-protein interactions by mass spectrometry) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative for GO annotation. While TPM3 clearly engages in multiple protein-protein interactions, more specific molecular function terms are preferred. High-throughput mass spectrometry interactome studies provide evidence for interactions but rarely characterize the functional nature of those interactions. Supporting Evidence: PMID:17353931 Large-scale mapping of human protein-protein interactions by mass spectrometry
GO:0005515 protein binding	IPI PMID:21516116 Next-generation sequencing to generate interactome datasets.	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:21516116 (next-generation sequencing for interactome datasets) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative. TPM3's functionally relevant interactions (with actin filaments, troponin complex components) are better captured by specific terms. Generic protein binding from large-scale interactome studies does not provide mechanistic insight. Supporting Evidence: PMID:21516116 Next-generation sequencing to generate interactome datasets
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:25416956 (proteome-scale map of the human interactome network) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative for GO annotation. Large-scale interactome mapping studies identify many interactions but the generic term does not convey functional information about TPM3's specific binding partners or the nature of those interactions. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:25910212 (macromolecular interaction perturbations in genetic disorders) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study examines disease-relevant interactions, the generic annotation does not capture the specific functional context of TPM3 interactions. Supporting Evidence: PMID:25910212 Widespread macromolecular interaction perturbations in human genetic disorders [interaction perturbation study]
GO:0005515 protein binding	IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:25959826 (interaction proteomics of neurodegenerative disease proteins) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative. This study focused on neurodegenerative disease proteins and TPM3 may have been identified as an interaction partner. However, the generic annotation does not provide functional insight. Supporting Evidence: PMID:25959826 Quantitative interaction proteomics of neurodegenerative disease proteins
GO:0005515 protein binding	IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:27107012 (Barcode Fusion Genetics pooled-matrix protein interaction screens) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. High-throughput screening methods identify many interactions but the generic term does not convey the functional significance of specific TPM3 interactions. Supporting Evidence: PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusion Genetics
GO:0005515 protein binding	IPI PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to ...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:29128334 (mitochondrial protein interactions linked to neurodegeneration) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study links mitochondrial interactions to neurodegeneration, the generic annotation does not provide functional insight into TPM3's role. TPM3's primary localization is cytoskeletal/actin filaments, not mitochondrial. Supporting Evidence: PMID:29128334 A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:31515488 (disruption of protein interactions by genetic variants) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study examines how genetic variants disrupt protein interactions, the generic annotation does not provide functional insight into specific TPM3 interactions. Supporting Evidence: PMID:31515488 Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:32296183 (reference map of the human binary protein interactome) uses the generic "protein binding" term from high-throughput interaction data. Reason: The term "protein binding" is uninformative for GO annotation. Reference interactome maps identify many binary interactions but the generic term does not convey functional significance. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:32814053 (interactome mapping of neurodegenerative disease proteins) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study focuses on neurodegeneration-related protein aggregation, the generic annotation does not specify the functional context of any TPM3 interactions identified. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:33961781 (dual proteome-scale networks for cell-specific interactome remodeling) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. While this study examines cell-specific interactome remodeling, the generic annotation does not convey functional information about TPM3 interactions. Supporting Evidence: PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:40205054 (multimodal cell maps for structural and functional genomics) uses the generic "protein binding" term. Reason: The term "protein binding" is uninformative. Large-scale multimodal cell mapping identifies interactions but the generic annotation does not provide functional insight into TPM3's role. Supporting Evidence: PMID:40205054 Multimodal cell maps as a foundation for structural and functional genomics
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MARK AS OVER ANNOTATED	Summary: This HTP annotation for mitochondrial localization is from a high-confidence human mitochondrial proteome study (PMID:34800366). However, TPM3's established localization is to actin filaments in the cytoskeleton. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location. Mitochondrial association may reflect high-throughput detection artifacts or transient/minor localization rather than a core functional site. Reason: TPM3 is primarily a cytoskeletal protein that binds to actin filaments. The mitochondrial localization identified in this high-throughput proteomics study may represent contamination, transient association, or a minor pool of protein. The primary functional localization of TPM3 is to actin filaments (muscle thin filaments or cytoskeletal actin), not mitochondria. This annotation should be viewed with caution. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0005515 protein binding	IPI PMID:35510366 Autosomal dominantly inherited myopathy likely caused by the...	MARK AS OVER ANNOTATED	Summary: PMID:35510366 supports a TPM3-TNNT1 interaction in a muscle thin-filament disease context, but the GO term used here is the generic protein binding term rather than a specific thin-filament or troponin/tropomyosin interaction term. Reason: The interaction is biologically relevant, but GO:0005515 is too generic to accept as a useful TPM3 molecular-function annotation. TPM3 already has specific actin filament binding and muscle thin-filament context annotations; this row should not be treated as core protein-binding function. Supporting Evidence: PMID:35510366 complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced file:human/TPM3/TPM3-uniprot.txt Interacts with TNNT1
GO:0005829 cytosol	TAS Reactome:R-HSA-9700179	KEEP AS NON CORE	Summary: This Reactome row describes cytosolic signaling context for oncogenic ALK fusion proteins that can use TPM3 as an N-terminal fusion partner, not native TPM3 actin-filament localization. Reason: Keep only as non-core fusion-protein/pathway context. Native TPM3 function is actin-filament binding and cytoskeletal/thin-filament regulation; the ALK fusion Reactome pathways should not be used as primary evidence for normal TPM3 localization. Supporting Evidence: Reactome:R-HSA-9700179 In addition to NPM, fusions with ALK have also been identified with EML4 file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0005829 cytosol	TAS Reactome:R-HSA-9700181	KEEP AS NON CORE	Summary: This Reactome row describes cytosolic signaling context for oncogenic ALK fusion proteins that can use TPM3 as an N-terminal fusion partner, not native TPM3 actin-filament localization. Reason: Keep only as non-core fusion-protein/pathway context. Native TPM3 function is actin-filament binding and cytoskeletal/thin-filament regulation; the ALK fusion Reactome pathways should not be used as primary evidence for normal TPM3 localization. Supporting Evidence: Reactome:R-HSA-9700181 After partner protein-mediated dimerization, ALK fusions are trans-autophosphorylated by the ALK kinase domain file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0005515 protein binding	IPI PMID:23892143 Human respiratory syncytial virus N, P and M protein interac...	MARK AS OVER ANNOTATED	Summary: This annotation from PMID:23892143 (RSV N, P and M protein interactions in HEK-293T cells) uses the generic "protein binding" term. This study focused on respiratory syncytial virus protein interactions, and TPM3 may have been identified as a cellular interaction partner. Reason: The term "protein binding" is uninformative. This study examined viral protein interactions and any TPM3 interactions identified likely represent host-pathogen interactions rather than TPM3's core cellular function. The generic annotation provides no functional insight. Supporting Evidence: PMID:23892143 Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: This HDA annotation for extracellular exosome localization derives from PMID:20458337, a study of MHC class II-associated proteins in B-cell exosomes. The study "identified 539 proteins" in exosomes from B cells. TPM3 detection in exosomes likely represents packaging of cytoskeletal components into exosomal cargo rather than a core functional localization. Reason: Detection of TPM3 in extracellular exosomes represents exosomal cargo packaging rather than a site of TPM3 function. Cytoskeletal proteins are commonly found in exosome proteomes. This is a valid observation but does not represent a core functional localization for TPM3, which primarily functions on actin filaments in the cytoskeleton. Supporting Evidence: PMID:20458337 we first analyzed the total proteome of highly purified B cell-derived exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins
GO:0005829 cytosol	TAS Reactome:R-HSA-390593	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: Reactome:R-HSA-390593 The cleft closes like a clam shell around the ATP molecule, triggering a large shape change that causes the myosin head to release actin
GO:0005829 cytosol	TAS Reactome:R-HSA-390595	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction
GO:0005829 cytosol	TAS Reactome:R-HSA-390597	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction
GO:0005829 cytosol	TAS Reactome:R-HSA-390598	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction
GO:0005829 cytosol	TAS Reactome:R-HSA-445699	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon
GO:0005829 cytosol	TAS Reactome:R-HSA-445700	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon
GO:0005829 cytosol	TAS Reactome:R-HSA-445704	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon
GO:0005829 cytosol	TAS Reactome:R-HSA-445705	KEEP AS NON CORE	Summary: This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle thin filament tropomyosin, or cytoskeleton localization. Reason: Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding protein. The specific functional locations are actin filament, muscle thin filament tropomyosin, cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures. Supporting Evidence: file:human/TPM3/TPM3-uniprot.txt Smooth muscle contraction is regulated by interaction with caldesmon
GO:0001725 stress fiber	IDA PMID:16236705 h2-Calponin is regulated by mechanical tension and modifies ...	UNDECIDED	Summary: Stress fiber localization is plausible for non-muscle cytoskeletal TPM3 isoforms, but the cached PMID:16236705 abstract supports h2-calponin effects on actin cytoskeleton rather than direct TPM3 stress-fiber localization. Reason: The available cached evidence does not directly establish TPM3 localization to stress fibers. This annotation should remain undecided unless the full text or GO source confirms that TPM3 itself was assayed in stress fibers, or a direct TPM3 localization source is added. Supporting Evidence: PMID:16236705 Force-expression of h2-calponin enhanced the resistance of the actin filaments to cytochalasin B treatment file:human/TPM3/TPM3-uniprot.txt In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments
GO:0005856 cytoskeleton	TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied...	ACCEPT	Summary: This TAS annotation for cytoskeleton localization derives from PMID:16130169, a proteomics study of HUVECs during etoposide-induced apoptosis. The study identified tropomyosin among proteins varying during apoptosis, indicating cytoskeletal involvement. The study confirmed "cellular functions more related to cell motility" among identified proteins. Reason: The cytoskeleton annotation is correct for TPM3, which is established as a cytoskeletal protein. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location. While more specific terms (actin filament, stress fiber) exist, this general term is acceptable. Supporting Evidence: PMID:16130169 illustrates various cellular functions more related to cell motility and angiogenesis file:human/TPM3/TPM3-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
GO:0005856 cytoskeleton	NAS PMID:3418707 Organization of the hTMnm gene. Implications for the evoluti...	ACCEPT	Summary: This NAS annotation for cytoskeleton derives from PMID:3418707, the foundational paper on hTMnm gene organization. The study characterized the gene producing both muscle and non-muscle (cytoskeletal) tropomyosin isoforms, clearly establishing TPM3's role in cytoskeletal function. The paper describes "TM30nm, a 248 amino acid cytoskeletal tropomyosin" in non-muscle cells. Reason: This annotation directly refers to TPM3's cytoskeletal function as established in the original characterization of the gene. The paper explicitly describes the cytoskeletal isoform TM30nm. This is a core localization for the non-muscle isoforms of TPM3. Supporting Evidence: PMID:3418707 In non-muscle tissue this gene produces a 2.5 kb (1 kb = 10(3) bases or base-pairs) mRNA encoding TM30nm, a 248 amino acid cytoskeletal tropomyosin
GO:0005862 muscle thin filament tropomyosin	TAS PMID:3018581 Tissue-specific expression of the human tropomyosin gene inv...	KEEP AS NON CORE	Summary: This TAS annotation for muscle thin filament tropomyosin derives from PMID:3018581, which characterized the tissue-specific expression of the TPM3 gene. The paper describes that in skeletal muscle, the gene produces "a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin" which functions as part of the muscle thin filament. Reason: This annotation is accurate for the skeletal muscle isoform (Isoform 1, 285 AA) but not for the cytoskeletal isoforms. The muscle thin filament tropomyosin complex is specific to muscle tissue where TPM3 Isoform 1 functions with the troponin complex for calcium-regulated contraction. Since this is isoform-specific, it represents a non-core localization. The core localization applicable to all isoforms is "actin filament" (GO:0005884). Supporting Evidence: PMID:3018581 a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle file:human/TPM3/TPM3-uniprot.txt Plays a central role, in association with the troponin complex, in the calcium dependent regulation of vertebrate striated muscle contraction file:human/TPM3/TPM3-deep-research-falcon.md Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament identity, and thin-filament regulation in muscle.

Core Functions

Actin filament binding is the fundamental molecular function of all TPM3 isoforms. Tropomyosins are coiled-coil proteins that bind along the length of actin filaments in both muscle and non-muscle cells. UniProt states "Binds to actin filaments in muscle and non-muscle cells" [UniProt P06753]. This function is conserved across the tropomyosin family (IBA evidence) and is essential for TPM3's roles in muscle contraction regulation and cytoskeletal stabilization.

Molecular Function:

actin filament binding

Directly Involved In:

actin filament organization

Cellular Locations:

actin filament

Supporting Evidence:

file:human/TPM3/TPM3-deep-research-falcon.md
Falcon report summarizes TPM3 as binding and stabilizing F-actin and regulating actin interactions with myosin and other actin-binding proteins.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

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:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:14743216

A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

PMID:16130169

Proteomics of human umbilical vein endothelial cells applied to etoposide-induced apoptosis.

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network.

PMID:16236705

h2-Calponin is regulated by mechanical tension and modifies the function of actin cytoskeleton.

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry.

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:21516116

Next-generation sequencing to generate interactome datasets.

PMID:23892143

Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25910212

Widespread macromolecular interaction perturbations in human genetic disorders.

PMID:25959826

Quantitative interaction proteomics of neurodegenerative disease proteins.

PMID:27107012

Pooled-matrix protein interaction screens using Barcode Fusion Genetics.

PMID:29128334

A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.

PMID:3018581

Tissue-specific expression of the human tropomyosin gene involved in the generation of the trk oncogene.

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

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PMID:33961781

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

PMID:3418707

Organization of the hTMnm gene. Implications for the evolution of muscle and non-muscle tropomyosins.

PMID:34800366

Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.

PMID:35510366

Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).

PMID:40205054

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

Reactome:R-HSA-390593

ATP Hydrolysis By Myosin

Reactome:R-HSA-390595

Calcium Binds Troponin-C

Reactome:R-HSA-390597

Release Of ADP From Myosin

Reactome:R-HSA-390598

Myosin Binds ATP

Reactome:R-HSA-445699

ATP Hydrolysis By Myosin

Reactome:R-HSA-445700

Myosin Binds ATP

Reactome:R-HSA-445704

Calcium Binds Caldesmon

Reactome:R-HSA-445705

Release Of ADP From Myosin

Reactome:R-HSA-9700179

Ligand-independent dimerization of ALK fusions

Reactome:R-HSA-9700181

Autophosphorylation of ALK fusions

file:human/TPM3/TPM3-deep-research-falcon.md

Falcon deep research on TPM3 function

TPM3 is an actin-filament binding coiled-coil tropomyosin whose isoforms stabilize and regulate distinct actin filament populations.

"Falcon report summarizes TPM3 as an actin-binding coiled-coil dimer that polymerizes along F-actin to stabilize filaments and regulate access of myosin and other actin-binding proteins."

file:human/TPM3/TPM3-uniprot.txt

UniProt record for human TPM3

Suggested Experiments

Experiment: Compare major TPM3 isoforms for F-actin binding, filament stabilization, myosin regulation, and protection from cofilin/gelsolin-mediated disassembly.

Hypothesis: Distinct TPM3 isoforms specify actin filament populations with different mechanical and regulatory properties.

Type: Isoform-specific actin filament assay

Experiment: Use long-read transcriptomics and targeted proteomics in slow skeletal muscle and non-muscle cells to map TPM3 isoform expression to GO-relevant functions.

Hypothesis: Muscle contraction annotations map mainly to skeletal muscle isoform 1, whereas cytoskeletal organization annotations map to shorter non-muscle isoforms.

Type: Endogenous isoform mapping

📚 Additional Documentation

Deep Research Falcon

(TPM3-deep-research-falcon.md)

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gene_id: TPM3
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AltName: Full=Tropomyosin-3; AltName: Full=Tropomyosin-5; Short=hTM5;'
gene_info: Name=TPM3;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the tropomyosin family. .
protein_domains: Tropomyosin. (IPR000533); Tropomyosin (PF00261)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P06753
Protein Description: RecName: Full=Tropomyosin alpha-3 chain; AltName: Full=Gamma-tropomyosin; AltName: Full=Tropomyosin-3; AltName: Full=Tropomyosin-5; Short=hTM5;
Gene Information: Name=TPM3;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the tropomyosin family. .
Key Domains: Tropomyosin. (IPR000533); Tropomyosin (PF00261)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "TPM3" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'TPM3' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene TPM3 (gene ID: TPM3, UniProt: P06753) in human.

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.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P06753
Protein Description: RecName: Full=Tropomyosin alpha-3 chain; AltName: Full=Gamma-tropomyosin; AltName: Full=Tropomyosin-3; AltName: Full=Tropomyosin-5; Short=hTM5;
Gene Information: Name=TPM3;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the tropomyosin family. .
Key Domains: Tropomyosin. (IPR000533); Tropomyosin (PF00261)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "TPM3" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene TPM3 (gene ID: TPM3, UniProt: P06753) in human.

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.

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.

Research report: Human TPM3 (UniProt P06753) — functional annotation, mechanisms, and current clinical relevance

Executive summary

Human TPM3 encodes tropomyosin alpha-3 chain (tropomyosin 3), an actin-binding, α-helical coiled-coil dimer that polymerizes along the length of F-actin to stabilize filaments and regulate access of myosin and other actin-binding proteins; in striated muscle it functions as part of the troponin–tropomyosin–actin thin filament regulatory system that underlies Ca2+-regulated contraction. (chen2024mechanismsoftropomyosin pages 1-2, chen2024mechanismsoftropomyosin pages 2-4, zhang2024congenitalmyopathiespathophysiological pages 7-8)

A major contemporary theme is that TPM3 isoforms “specify” distinct actin filament populations, yielding isoform-dependent mechanical and signaling outputs in both muscle and non-muscle contexts (e.g., epithelial adherens junction-associated actomyosin). (chen2024mechanismsoftropomyosin pages 2-4)

Clinically, TPM3 is relevant in two distinct ways: (i) germline TPM3 variants cause congenital myopathies (notably nemaline myopathy) by perturbing actin–tropomyosin interactions and thin filament stability/regulation; and (ii) somatic TPM3::NTRK1 and other TPM3 kinase fusions (ALK, ROS1) act as oncogenic drivers and are actionable with TRK inhibitors when NTRK-fusion positive. (chen2024mechanismsoftropomyosin pages 6-8, zhang2024congenitalmyopathiespathophysiological pages 7-8, NCT02576431 chunk 1)

Identity verification (mandatory)

Target gene/protein matches the user-provided UniProt context. Recent peer-reviewed sources explicitly describe TPM3 as human tropomyosin 3 / tropomyosin alpha-3, a member of the tropomyosin family characterized by α-helical coiled-coil dimers that bind actin filaments. (chen2024mechanismsoftropomyosin pages 1-2, chen2024mechanismsoftropomyosin pages 2-4)

A 2024 review places TPM3 at chromosome 1q21.3, reporting 14 exons spanning ~39 kb and extensive alternative splicing. (chen2024mechanismsoftropomyosin pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Tropomyosin / TPM3 as an actin-filament “regulatory coat”

Tropomyosins are actin-binding proteins that assemble as coiled-coil dimers and align head-to-tail to form continuous polymers along F-actin. TPM3’s core biochemical role is to stabilize actin filaments and regulate actin’s functional interactions with myosin and other actin-binding proteins. (chen2024mechanismsoftropomyosin pages 1-2, chen2024mechanismsoftropomyosin pages 2-4)

Mechanisms attributed to TPM3 in recent syntheses include:
- Regulation of actin–myosin ATPase activity and the Ca2+-dependent thin filament switch through interaction with troponin, creating a Ca2+-sensitive steric barrier on actin. (chen2024mechanismsoftropomyosin pages 1-2)
- Protection against filament severing/disassembly, including protection from gelsolin-mediated cleavage and ADF/cofilin-dependent depolymerization, and reported inhibition of Arp2/3-mediated branching nucleation (isoform- and context-dependent). (chen2024mechanismsoftropomyosin pages 2-4)

These mechanistic points support annotating TPM3 as a non-enzymatic structural/regulatory protein, rather than a catalytic enzyme or transporter.

1.2 Isoforms and isoform logic

TPM3 is notable for extensive isoform diversity via alternative splicing. A 2024 review reports TPM3 produces approximately 27 transcripts, and summarizes ten TPM3 “isotypes” (isoform classes) with exon usage in its Table 1. (chen2024mechanismsoftropomyosin pages 1-2, chen2024mechanismsoftropomyosin media 37fbd59e, chen2024mechanismsoftropomyosin media 4ca11536)

Key quantitative isoform properties reported in 2024 include:
- Cytoskeletal TPM3 products of 247–248 amino acids (~28–30 kDa)
- A high-molecular-weight (HMW) TPM3 form of 285 amino acids (~34 kDa) (chen2024mechanismsoftropomyosin pages 1-2)

This isoform multiplicity is central to current thinking: different tropomyosin isoforms can tune actin filament function by regulating the binding of myosin motors and actin-binding proteins, thereby producing functionally distinct actin filament populations. (chen2024mechanismsoftropomyosin pages 10-11, chen2024mechanismsoftropomyosin pages 2-4)

2) Localization, expression, and pathway/complex context

2.1 Subcellular localization

Across muscle and non-muscle cells, TPM3 localizes to actin microfilaments (including actomyosin bundles). (chen2024mechanismsoftropomyosin pages 8-10)

Recent summaries highlight specific TPM3-enriched actin structures:
- Epithelial zonula adherens (ZA)-linked cytoskeleton, consistent with roles in adhesion-associated actomyosin organization and epithelial mechanics. (chen2024mechanismsoftropomyosin pages 2-4)
- Cortical actin contexts (e.g., during oocyte maturation) and perinuclear/organelle-associated actin reorganization in certain settings. (chen2024mechanismsoftropomyosin pages 2-4)

In cancer histology summarized by Chen et al. (2024), TPM3 protein signal is described as predominantly cytoplasmic in hepatocellular carcinoma cells, consistent with cytoskeletal localization. (chen2024mechanismsoftropomyosin pages 4-5)

2.2 Tissue and fiber-type expression

In the congenital myopathy review by Zhang et al. (2024), TPM3 is described as encoding a muscle fiber-specific α-tropomyosin isoform in type I (slow) fibers, with higher expression in slow vs fast fibers (65% vs 29%) in the cited evidence base. (zhang2024congenitalmyopathiespathophysiological pages 7-8)

A TPM3-focused 2024 review further notes that HMW TPM3 is strongly expressed in skeletal muscle and described as scarce/low in tissues such as liver/brain/lung (within the review’s synthesis). (chen2024mechanismsoftropomyosin pages 1-2)

2.3 Pathways and complexes

The dominant pathway/complex context for TPM3 is the thin filament regulatory system:
- Actin–tropomyosin–troponin functional unit that regulates myosin access to actin in response to Ca2+ (striated muscle contraction regulation). (chen2024mechanismsoftropomyosin pages 1-2, zhang2024congenitalmyopathiespathophysiological pages 7-8)

Non-muscle pathway context in current syntheses emphasizes TPM3’s role in actomyosin bundles and ZA-linked cytoskeleton, aligning TPM3 biology with mechanotransduction and cell-shape control. (chen2024mechanismsoftropomyosin pages 2-4)

3) Recent developments and latest research (prioritizing 2023–2024)

Chen et al. (2024) emphasize that short cytoskeletal TPM3 isoforms (e.g., Tpm3.1/Tpm3.2) are relatively dynamic on actin filaments and may differentially affect actomyosin function; one described effect is stimulation of non-muscle myosin IIa ATPase (isoform-specific). (chen2024mechanismsoftropomyosin pages 2-4)

This direction aligns with the broader trend of viewing tropomyosin isoforms as “filament identity” determinants that pattern actin networks.

3.2 Myopathy mechanisms: actin affinity and structural instability

Zhang et al. (2024) report that a TPM3 M9R missense mutation linked to late-onset childhood nemaline myopathy weakens TPM3–actin affinity and yields local structural instability, exemplifying a mechanistic bridge from single-residue changes to thin filament dysfunction. (zhang2024congenitalmyopathiespathophysiological pages 7-8)

3.3 Precision oncology: TPM3 as a recurrent fusion partner

In cancer, the key recent consolidation is that TPM3 is a recurrent 5′ fusion partner that provides dimerization/coiled-coil capacity enabling constitutive activation of fused kinases (e.g., NTRK1, ALK, ROS1). (chen2024mechanismsoftropomyosin pages 4-5, chen2024mechanismsoftropomyosin pages 8-10)

4) Applications and real-world implementations

4.1 Diagnostics: detection of TPM3 rearrangements

TPM3’s most direct real-world implementation is as a fusion partner detectable by clinical NGS panels, frequently supported by pan-TRK immunohistochemistry when NTRK fusions are suspected. (vince2024beyondclinicaltrials pages 4-6)

CRC-focused guidance reviews list TPM3 among common NTRK fusion partners and position NTRK fusions as actionable rare variants. (chen2024progressinclinical pages 1-2)

4.2 Therapeutics: TRK inhibitors in NTRK-fusion cancers (including TPM3::NTRK1)

ClinicalTrials.gov records document broad implementation of tumor-agnostic TRK inhibition in NTRK-fusion tumors:
- Larotrectinib basket study NAVIGATE (Phase 2; n=215; NCT02576431; continuous oral dosing), enrolling solid tumors harboring NTRK1/2/3 fusions including CRC and sarcoma arms. (NCT02576431 chunk 1)
- Pediatric SCOUT trial (Phase 1/2; n=154; NCT02637687) for pediatric NTRK-fusion solid and CNS tumors, primary completion listed as 2024-07-20 in the record. (NCT02637687 chunk 1)
- Adult larotrectinib Phase 1 trial (NCT02122913; n=75). (NCT02122913 chunk 1)
- Entrectinib basket study STARTRK-2 (Phase 2; n=534; NCT02568267), enrolling NTRK/ROS1/ALK rearranged tumors. (NCT02568267 chunk 1)

Expanded access programs are also documented for both agents (e.g., entrectinib EAP NCT03066661). (NCT03066661 chunk 1)

A 2024 real-world pediatric oncology report (Brazil) provides practical implementation insights—testing access, funding pathways, and outcomes—in 17 NTRK-fused tumors treated with larotrectinib. (vince2024beyondclinicaltrials pages 1-2)

5) Statistics and quantitative data from recent sources

5.1 TPM3 gene and isoform quantitative descriptors

A 2024 TPM3 review reports: 14 exons, ~39 kb genomic span, ~27 transcripts, and major TPM3 isoform sizes of 247–248 aa (28–30 kDa) and 285 aa (34 kDa). (chen2024mechanismsoftropomyosin pages 1-2)

The review’s Figure 1 and Table 1 visually summarize gene structure and isoform/isotype exon usage. (chen2024mechanismsoftropomyosin media 37fbd59e, chen2024mechanismsoftropomyosin media 4ca11536)

5.2 Muscle fiber-type expression statistic

A 2024 congenital myopathy review reports TPM3 is a slow-fiber-associated α-tropomyosin, with higher expression in slow vs fast fibers (65% vs 29%) in the cited evidence base. (zhang2024congenitalmyopathiespathophysiological pages 7-8)

5.3 NTRK fusion frequencies and TPM3::NTRK1 context

In colorectal cancer, a 2024 review reports overall NTRK fusion frequency of 0.2%–2.4%, listing TPM3 among common NTRK fusion partners. (chen2024progressinclinical pages 1-2)

5.4 Real-world TRK inhibitor outcomes (pediatric cohort)

A 2024 real-world cohort of 17 pediatric/adolescent NTRK-fused tumors treated with larotrectinib reported centrally reviewed objective responses in 11/14 evaluable patients (2 complete responses, 9 partial responses) and 3 stable disease, with 15/17 alive at median 25 months follow-up. (vince2024beyondclinicaltrials pages 1-2)

Within that same report, TPM3::NTRK1 accounted for four sarcoma cases among the 17-patient cohort. (vince2024beyondclinicaltrials pages 4-6)

5.5 Pharmacovigilance statistics for TRK inhibitors

A 2024 genome-based and real-world pharmacovigilance analysis reports FAERS adverse event (ADE) counts of 524 (larotrectinib) and 563 (entrectinib), with median ADE onset times of 44 days (larotrectinib; IQR 7–136) and 16 days (entrectinib; IQR 6–86.5). (cui2024fromgenomicspectrum pages 1-2)

Expert interpretation and synthesis

Current authoritative syntheses converge on a functional model where TPM3’s “primary function” is regulatory—stabilizing and tuning actin filament behavior rather than catalysis. In muscle, the most conservative interpretation is that TPM3’s essential role is to help implement Ca2+-regulated thin filament activation by controlling tropomyosin positioning along actin together with troponin. (chen2024mechanismsoftropomyosin pages 1-2, zhang2024congenitalmyopathiespathophysiological pages 7-8)

Beyond muscle, the most influential contemporary concept is isoform-coded actin filament identity: TPM3 isoforms are posited to gate the binding and activity of ABPs and myosins, thereby shaping architecture and mechanics of actin networks such as adherens-junction-associated bundles. (chen2024mechanismsoftropomyosin pages 2-4)

Clinically, TPM3 is a compelling example of a gene whose native structural role is distinct from its oncogenic fusion role: TPM3 itself is not a kinase, but its coiled-coil/oligomerization properties can activate fused kinases (e.g., NTRK1), enabling tumor-agnostic targeted therapy strategies. (chen2024mechanismsoftropomyosin pages 4-5, NCT02576431 chunk 1)

Embedded structured summary

The following table consolidates the main functional-annotation points, statistics, and real-world implementations.

Category	Summary
Identity/Family	- Verified target: human TPM3 encodes tropomyosin 3 / tropomyosin alpha-3 chain, a member of the tropomyosin family of actin-binding, α-helical coiled-coil proteins; chromosome 1q21.3 is reported in recent reviews (chen2024mechanismsoftropomyosin pages 1-2, chen2024mechanismsoftropomyosin pages 2-4). - TPM3 is distinct from NTRK/TRK genes; in cancer it often appears as the 5′ fusion partner in TPM3::NTRK1, but the native gene product is a structural/regulatory actin-filament protein, not a kinase (chen2024mechanismsoftropomyosin pages 6-8, chen2024mechanismsoftropomyosin pages 8-10).
Molecular function	- Primary role is binding and stabilizing F-actin and regulating actin’s interactions with myosin and other actin-binding proteins (chen2024mechanismsoftropomyosin pages 1-2, chen2024mechanismsoftropomyosin pages 2-4, chen2024mechanismsoftropomyosin pages 8-10). - In muscle, TPM3 helps regulate actin–myosin ATPase activity and, together with troponin, forms a Ca2+-sensitive barrier/switch on thin filaments (chen2024mechanismsoftropomyosin pages 1-2). - In non-muscle cells, TPM3 contributes to actomyosin-dependent processes including cell movement, adhesion, vesicle trafficking, and tissue organization (chen2024mechanismsoftropomyosin pages 8-10).
Mechanism on actin/thin filament	- TPM3 decorates actin filaments longitudinally, helping specify functionally distinct actin filament populations and tune access of myosin/ABPs to the filament (chen2024mechanismsoftropomyosin pages 10-11, chen2024mechanismsoftropomyosin pages 2-4). - Reported mechanisms include inhibition of Arp2/3-mediated branching, protection from gelsolin-mediated severing, and protection from ADF/cofilin-driven depolymerization (chen2024mechanismsoftropomyosin pages 2-4, chen2024mechanismsoftropomyosin pages 1-2). - Isoform-specific effects matter: short isoforms such as Tpm3.1/Tpm3.2 are dynamic on filaments, and Tpm3.12 showed greater Ca2+ sensitivity than Tpm1.1 in in vitro motility assays (chen2024mechanismsoftropomyosin pages 2-4, haas2026sarcomericremodellingin pages 13-16).
Key isoforms/sizes	- Recent review reports TPM3 spans 14 exons over ~39 kb and can generate ~27 transcripts by alternative splicing (chen2024mechanismsoftropomyosin pages 1-2). - Reported major products include cytoskeletal isoforms of 247–248 aa (~28–30 kDa) and a high-molecular-weight form of 285 aa (~34 kDa) (chen2024mechanismsoftropomyosin pages 1-2). - Named isoforms include Tpm3.1, Tpm3.2, Tpm3.4, Tpm3.5, Tpm3.7, Tpm3.8, Tpm3.9, Tpm3.12, Tpm3.13; Table 1/Figure 1 in the 2024 review summarize isoform architecture (chen2024mechanismsoftropomyosin pages 1-2, chen2024mechanismsoftropomyosin media 37fbd59e, chen2024mechanismsoftropomyosin media 4ca11536).
Subcellular localization	- TPM3 localizes to actin microfilaments/thin filaments in both muscle and non-muscle cells (chen2024mechanismsoftropomyosin pages 8-10). - Specific reported sites include the epithelial zonula adherens (ZA)-linked cytoskeleton, cortical actin during oocyte maturation, and other actomyosin bundle systems (chen2024mechanismsoftropomyosin pages 2-4). - In some tumor studies summarized by the review, TPM3 protein was noted as predominantly cytoplasmic (chen2024mechanismsoftropomyosin pages 4-5).
Tissue/cell expression	- TPM3 encodes a muscle fiber–specific α-tropomyosin isoform in type I slow fibers; one review reports higher expression in slow vs fast fibers (65% vs 29%) (zhang2024congenitalmyopathiespathophysiological pages 7-8). - HMW TPM3 expression is described as strong in skeletal muscle and relatively low/scarce in liver, brain, and lung (chen2024mechanismsoftropomyosin pages 1-2). - Single-nucleus/long-read work detected TPM3 in human cardiomyocytes and reported that TPM3 products increase in heart failure, approaching TPM1 abundance in remodeled sarcomeric programs (haas2026sarcomericremodellingin pages 13-16).
Pathways/complexes	- Core complex/pathway context is the troponin–tropomyosin–actin thin filament regulatory system that controls contractility in striated muscle (chen2024mechanismsoftropomyosin pages 1-2, zhang2024congenitalmyopathiespathophysiological pages 7-8). - In non-muscle contexts, TPM3 participates in actomyosin bundles and ZA-linked cytoskeletal networks that regulate epithelial mechanics and morphogenesis (chen2024mechanismsoftropomyosin pages 2-4). - Protein-interaction analyses link TPM3 with actins (ACTA1/ACTC1), troponins, TPM1, and in fusion-positive cancers with NTRK1, consistent with both physiologic cytoskeletal and pathologic fusion contexts (chen2024mechanismsoftropomyosin pages 8-10, chen2024mechanismsoftropomyosin pages 6-8).
Disease associations—myopathy	- TPM3 mutations are established causes of congenital myopathies, especially nemaline myopathy, and are also linked to cap myopathy, congenital fiber type disproportion, distal nemaline/cap phenotypes, and muscle stiffness/hypercontractility phenotypes in cited literature (chen2024mechanismsoftropomyosin pages 12-12, chen2024mechanismsoftropomyosin pages 10-11, zhang2024congenitalmyopathiespathophysiological pages 7-8). - A 2024 review notes a TPM3 M9R missense mutation causing childhood late-onset nemaline myopathy by weakening actin affinity and destabilizing local structure (zhang2024congenitalmyopathiespathophysiological pages 7-8). - Another 2024 review summarized TPM3-related congenital muscle disorders as including congenital fiber type disorder (51%) and linear myopathy (29%) among reported cases in the literature it surveyed (chen2024mechanismsoftropomyosin pages 6-8).
Disease associations—oncogenic fusions	- TPM3 is a recurrent oncogenic fusion partner with NTRK1, ALK, and ROS1; the TPM3 coiled-coil region can promote dimerization/constitutive activation of the fused kinase (chen2024mechanismsoftropomyosin pages 2-4, chen2024mechanismsoftropomyosin pages 4-5, chen2024mechanismsoftropomyosin pages 8-10). - TPM3::NTRK1 is recurrent in spindle cell neoplasms and other solid tumors; a 2024 review cites 54% TPM3-NTRK1 among adult NTRK-rearranged cervical spindle cell tumors, with the cervix accounting for 62% of such tumors in the cited series (chen2024mechanismsoftropomyosin pages 6-8). - In CRC, NTRK fusions are rare overall (0.2%–2.4%), and TPM3 is one of the recognized partner genes; one review also cites historical reports of ~1.5% TPM3-NTRK1 rearrangement incidence in CRC literature (chen2024progressinclinical pages 1-2).
Applications/clinical implementation	- Diagnostic application: TPM3 rearrangements are clinically actionable biomarkers detected by NGS, often supported by pan-TRK IHC in fusion-positive tumors (vince2024beyondclinicaltrials pages 4-6, cui2024fromgenomicspectrum pages 1-2). - Therapeutic implementation: first-generation TRK inhibitors larotrectinib and entrectinib are used for NTRK fusion–positive cancers, including TPM3::NTRK1-positive tumors (cui2024fromgenomicspectrum pages 1-2, NCT02576431 chunk 1, NCT02568267 chunk 1). - Ongoing/landmark studies include larotrectinib NAVIGATE (Phase 2, n=215), pediatric SCOUT (Phase 1/2, n=154), adult Phase 1 larotrectinib (n=75), and entrectinib STARTRK-2 (Phase 2, n=534); expanded-access programs also existed for both drugs (NCT02637687 chunk 1, NCT02122913 chunk 1, NCT02576431 chunk 1, NCT03066661 chunk 1, NCT02568267 chunk 1).
Quantitative statistics	- Pediatric real-world larotrectinib cohort: 17 patients with NTRK-fused tumors; radiology review in 14 showed 11/14 objective responses (2 CR, 9 PR) and 3 SD; 15/17 were alive at median 25 months follow-up (vince2024beyondclinicaltrials pages 1-2). - In that cohort, TPM3::NTRK1 accounted for 4 sarcoma cases; ETV6::NTRK3 was also seen in 4 sarcomas plus 2 glioneuronal tumors (vince2024beyondclinicaltrials pages 4-6). - Pharmacovigilance data summarized 524 larotrectinib and 563 entrectinib ADE reports; median ADE onset was 44 days for larotrectinib and 16 days for entrectinib (cui2024fromgenomicspectrum pages 1-2).

Table: This table condenses the key functional annotation points for human TPM3 (UniProt P06753), including verified identity, actin/thin-filament mechanism, localization, disease relevance, and clinically actionable fusion biology. It is designed to support a final narrative report with high-density, citation-backed facts.

Key visual evidence (from 2024 review)

TPM3 gene schematic and isoform/isotype exon usage summary (Figure 1 and Table 1). (chen2024mechanismsoftropomyosin media 37fbd59e, chen2024mechanismsoftropomyosin media 4ca11536)

Primary sources cited (URLs; publication dates)

Chen A et al. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon. 2024-08. https://doi.org/10.1016/j.heliyon.2024.e35723 (chen2024mechanismsoftropomyosin pages 1-2)
Zhang H et al. Congenital myopathies: pathophysiological mechanisms and promising therapies. Journal of Translational Medicine. 2024-09. https://doi.org/10.1186/s12967-024-05626-5 (zhang2024congenitalmyopathiespathophysiological pages 7-8)
Vince CSC et al. Beyond clinical trials… real-world pediatric oncology. JCO Precision Oncology. 2024-05. https://doi.org/10.1200/po.23.00713 (vince2024beyondclinicaltrials pages 1-2)
Chen S et al. Progress in clinical diagnosis and treatment of colorectal cancer with rare genetic variants. Cancer Biology & Medicine. 2024-06. https://doi.org/10.20892/j.issn.2095-3941.2024.0026 (chen2024progressinclinical pages 1-2)
Cui Z et al. From genomic spectrum of NTRK genes to adverse effects of its inhibitors… Frontiers in Pharmacology. 2024-01. https://doi.org/10.3389/fphar.2024.1329409 (cui2024fromgenomicspectrum pages 1-2)
ClinicalTrials.gov: NCT02576431 (larotrectinib NAVIGATE; Phase 2), NCT02637687 (larotrectinib SCOUT; Phase 1/2), NCT02568267 (entrectinib STARTRK-2; Phase 2), NCT03066661 (entrectinib expanded access). https://clinicaltrials.gov (NCT02637687 chunk 1, NCT02576431 chunk 1, NCT02568267 chunk 1, NCT03066661 chunk 1)

References

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(chen2024mechanismsoftropomyosin pages 2-4): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.
(zhang2024congenitalmyopathiespathophysiological pages 7-8): Han Zhang, Mengyuan Chang, Daiyue Chen, Jiawen Yang, Yijie Zhang, Jiacheng Sun, Xinlei Yao, Hualin Sun, Xiaosong Gu, Meiyuan Li, Yuntian Shen, and Bin Dai. Congenital myopathies: pathophysiological mechanisms and promising therapies. Journal of Translational Medicine, Sep 2024. URL: https://doi.org/10.1186/s12967-024-05626-5, doi:10.1186/s12967-024-05626-5. This article has 15 citations and is from a peer-reviewed journal.
(chen2024mechanismsoftropomyosin pages 6-8): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.
(NCT02576431 chunk 1): A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors. Bayer. 2015. ClinicalTrials.gov Identifier: NCT02576431
(chen2024mechanismsoftropomyosin media 37fbd59e): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.
(chen2024mechanismsoftropomyosin media 4ca11536): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.
(chen2024mechanismsoftropomyosin pages 10-11): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.
(chen2024mechanismsoftropomyosin pages 8-10): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.
(chen2024mechanismsoftropomyosin pages 4-5): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.
(vince2024beyondclinicaltrials pages 4-6): Carolina Sgarioni Camargo Vince, Maria Sol Brassesco, Bruna Minniti Mançano, Lauro Jose Gregianin, Edna Kakitani Carbone, Adham do Amaral e Castro, Viviane Sayuri Yamachira Dwan, Roberta Zeppini Menezes da Silva, Cassia Silvestre Mariano, Juliana França da Mata, Marcelo Oliveira Silva, Eliana Maria Monteiro Caran, Carla Donato Macedo, Gildene Alves da Costa, Tereza Cristina Esteves, Luciana Nunes Silva, Sima Esther Ferman, Flavia Delgado Martins, Lilian Maria Cristófani, Vicente Odone-Filho, Marcelo Milone Silva, Rui Manuel Reis, Mara Albonei Dudeque Pianovski, Paulo Vidal Campregher, Mayara Satsuki Kunii, Karla Emilia de Sá Rodrigues, Neviçolino Pereira Carvalho Filho, and Elvis Terci Valera. Beyond clinical trials: understanding neurotrophic tropomyosin receptor kinase inhibitor challenges and efficacy in real-world pediatric oncology. JCO Precision Oncology, May 2024. URL: https://doi.org/10.1200/po.23.00713, doi:10.1200/po.23.00713. This article has 5 citations and is from a peer-reviewed journal.
(chen2024progressinclinical pages 1-2): Shuyi Chen, Jing Gu, Kaichun Wu, Xiaodi Zhao, and Yuanyuan Lu. Progress in clinical diagnosis and treatment of colorectal cancer with rare genetic variants. Cancer Biology & Medicine, pages 473-483, Jun 2024. URL: https://doi.org/10.20892/j.issn.2095-3941.2024.0026, doi:10.20892/j.issn.2095-3941.2024.0026. This article has 8 citations.
(NCT02637687 chunk 1): A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children. Bayer. 2015. ClinicalTrials.gov Identifier: NCT02637687
(NCT02122913 chunk 1): A Study to Test the Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer. Bayer. 2014. ClinicalTrials.gov Identifier: NCT02122913
(NCT02568267 chunk 1): Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangements (Fusions). Hoffmann-La Roche. 2015. ClinicalTrials.gov Identifier: NCT02568267
(NCT03066661 chunk 1): Expanded Access to Entrectinib for Cancers With NTRK1/2/3, ROS1, or ALK Gene Fusions. Hoffmann-La Roche. ClinicalTrials.gov Identifier: NCT03066661
(vince2024beyondclinicaltrials pages 1-2): Carolina Sgarioni Camargo Vince, Maria Sol Brassesco, Bruna Minniti Mançano, Lauro Jose Gregianin, Edna Kakitani Carbone, Adham do Amaral e Castro, Viviane Sayuri Yamachira Dwan, Roberta Zeppini Menezes da Silva, Cassia Silvestre Mariano, Juliana França da Mata, Marcelo Oliveira Silva, Eliana Maria Monteiro Caran, Carla Donato Macedo, Gildene Alves da Costa, Tereza Cristina Esteves, Luciana Nunes Silva, Sima Esther Ferman, Flavia Delgado Martins, Lilian Maria Cristófani, Vicente Odone-Filho, Marcelo Milone Silva, Rui Manuel Reis, Mara Albonei Dudeque Pianovski, Paulo Vidal Campregher, Mayara Satsuki Kunii, Karla Emilia de Sá Rodrigues, Neviçolino Pereira Carvalho Filho, and Elvis Terci Valera. Beyond clinical trials: understanding neurotrophic tropomyosin receptor kinase inhibitor challenges and efficacy in real-world pediatric oncology. JCO Precision Oncology, May 2024. URL: https://doi.org/10.1200/po.23.00713, doi:10.1200/po.23.00713. This article has 5 citations and is from a peer-reviewed journal.
(cui2024fromgenomicspectrum pages 1-2): Zhiwei Cui, Zhen Zhai, De Xie, Lihui Wang, Feiyan Cheng, Siyu Lou, Fan Zou, Rumeng Pan, Shixue Chang, Haoyan Yao, Jing She, Yidan Zhang, and Xinyuan Yang. From genomic spectrum of ntrk genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis. Frontiers in Pharmacology, Jan 2024. URL: https://doi.org/10.3389/fphar.2024.1329409, doi:10.3389/fphar.2024.1329409. This article has 12 citations.
(haas2026sarcomericremodellingin pages 13-16): Jan Haas, Sarah Schudy, Benedikt Rauscher, Ana Munoz, Steffen Roßkopf, Christoph Reich, Gizem Donmez Yalcin, Abdullah Yalcin, Timon Seeger, Manuel H. Taft, Marc Freichel, Dirk Grimm, Dietmar Manstein, Johannes Backs, Norbert Frey, Lars Steinmetz, and Benjamin Meder. Sarcomeric remodelling in human heart failure unraveled by single molecule long read sequencing. BioRxiv, Mar 2026. URL: https://doi.org/10.1101/2025.02.28.640805, doi:10.1101/2025.02.28.640805. This article has 2 citations.
(chen2024mechanismsoftropomyosin pages 12-12): Anjie Chen, Sixin Li, Jiandong Gui, Hangsheng Zhou, Lijie Zhu, and Yuanyuan Mi. Mechanisms of tropomyosin 3 in the development of malignant tumors. Heliyon, 10:e35723, Aug 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e35723, doi:10.1016/j.heliyon.2024.e35723. This article has 4 citations.

Citations

chen2024mechanismsoftropomyosin pages 2-4
chen2024mechanismsoftropomyosin pages 1-2
chen2024mechanismsoftropomyosin pages 8-10
chen2024mechanismsoftropomyosin pages 4-5
zhang2024congenitalmyopathiespathophysiological pages 7-8
vince2024beyondclinicaltrials pages 4-6
chen2024progressinclinical pages 1-2
vince2024beyondclinicaltrials pages 1-2
cui2024fromgenomicspectrum pages 1-2
haas2026sarcomericremodellingin pages 13-16
chen2024mechanismsoftropomyosin pages 6-8
chen2024mechanismsoftropomyosin pages 10-11
chen2024mechanismsoftropomyosin pages 12-12
https://doi.org/10.1016/j.heliyon.2024.e35723
https://doi.org/10.1186/s12967-024-05626-5
https://doi.org/10.1200/po.23.00713
https://doi.org/10.20892/j.issn.2095-3941.2024.0026
https://doi.org/10.3389/fphar.2024.1329409
https://clinicaltrials.gov
https://doi.org/10.1016/j.heliyon.2024.e35723,
https://doi.org/10.1186/s12967-024-05626-5,
https://doi.org/10.1200/po.23.00713,
https://doi.org/10.20892/j.issn.2095-3941.2024.0026,
https://doi.org/10.3389/fphar.2024.1329409,
https://doi.org/10.1101/2025.02.28.640805,

Notes

(TPM3-notes.md)

TPM3 (Tropomyosin 3) Notes - ISOFORMS Project

Key Isoform Biology

TPM3 has 7 named isoforms with tissue-specific expression, similar to TPM1.

Tissue-Specific Isoforms

Isoform	UniProt ID	Synonym	Tissue	Key Feature
Isoform 1	P06753-1	Skeletal muscle	Slow skeletal muscle	Type I fibers
Isoform 2	P06753-2	TM30nm, Cytoskeletal	Non-muscle cells	30nm variant

Functional Distinctions

Skeletal muscle isoform (1):
- Expressed in slow-twitch (type I) muscle fibers
- Part of thin filament regulatory complex
- Essential for proper muscle contraction

Cytoskeletal isoforms (2, 3, etc.):
- TM30nm - shorter variant (248 AA vs 285 AA for muscle)
- Functions in non-muscle actin cytoskeleton
- Different actin binding characteristics

Disease Associations

CMYO4A: Congenital myopathy 4A
- Autosomal dominant
- Muscle weakness in infancy/childhood
- Features: hypotonia, respiratory insufficiency
- Muscle biopsy shows nemaline rods, "cap" structures, fiber-type disproportion

UniProt states:

"A muscular disorder characterized by onset of muscle weakness in infancy or childhood. Most affected individuals show mildly delayed motor development, hypotonia, generalized muscle weakness"

Relationship to TPM1

TPM1 and TPM3 are both members of the tropomyosin family but:
- TPM1: More associated with cardiac/smooth muscle function
- TPM3: More associated with slow skeletal muscle and cytoskeleton

Expected Annotation Issues

"Muscle contraction" - applies to muscle isoforms
"Actin binding" - all isoforms but with different properties
"Cytoskeleton organization" - primarily cytoskeletal isoforms

GOA Annotation Count: 39

📄 View Raw YAML

id: P06753
gene_symbol: TPM3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'TPM3 (Tropomyosin 3) is a coiled-coil actin-binding protein with 7 tissue-specific isoforms.
  ISOFORM BIOLOGY: (1) Isoform 1 (P06753-1) is expressed in SLOW SKELETAL MUSCLE (type I fibers); (2)
  Isoform 2 (TM30nm, P06753-2) is the shorter CYTOSKELETAL form (248 AA vs 285 AA for muscle). The muscle
  isoform is part of the thin filament regulatory complex essential for muscle contraction in slow-twitch
  fibers. The cytoskeletal TM30nm variant has different actin binding properties and functions in non-muscle
  cells. DISEASE: Mutations cause Congenital myopathy 4A (CMYO4A) with nemaline rods, cap structures,
  and fiber-type disproportion. Annotations for "muscle contraction" apply to muscle isoforms; "actin
  cytoskeleton" applies primarily to cytoskeletal isoforms.'
existing_annotations:
- term:
    id: GO:0051015
    label: actin filament binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: TPM3 is a well-established actin-binding protein. UniProt states "Binds to actin
      filaments in muscle and non-muscle cells" [UniProt P06753]. Both the muscle isoform (285 AA)
      and cytoskeletal TM30nm isoform (248 AA) bind actin filaments, though with different
      properties. PMID:3018581 confirms tissue-specific expression with "a 2.5-kilobase (kb) mRNA
      encoding a 248-amino-acid tropomyosin in human fibroblasts" (cytoskeletal) and "a 1.3-kb mRNA
      encoding a 285-amino-acid tropomyosin in human skeletal muscle." This is a core molecular
      function shared across all isoforms.
    action: ACCEPT
    reason: Actin filament binding is a fundamental molecular function of all tropomyosin isoforms.
      The IBA annotation is well-supported by the phylogenetic conservation of this function across
      the tropomyosin family and direct experimental evidence from multiple studies. This represents
      a core function of TPM3.
    supported_by:
    - reference_id: PMID:3018581
      supporting_text: a 2.5-kilobase (kb) mRNA encoding a 248-amino-acid tropomyosin in human
        fibroblasts and a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Binds to actin filaments in muscle and non-muscle cells
    - reference_id: file:human/TPM3/TPM3-deep-research-falcon.md
      supporting_text: >-
        Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament
        identity, and thin-filament regulation in muscle.
- term:
    id: GO:0007015
    label: actin filament organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      TPM3 contributes to actin filament organization in both muscle and non-muscle contexts. UniProt
      states that in non-muscle cells TPM3 is implicated in stabilizing cytoskeleton actin filaments,
      while the muscle isoform contributes to thin-filament regulation. This process annotation appropriately
      captures the conserved role of tropomyosins in organizing actin filament architecture.
    action: ACCEPT
    reason: Actin filament organization is a well-supported biological process for TPM3. The IBA
      annotation reflects the conserved role of tropomyosins in organizing and stabilizing actin
      filament structures. This applies to both muscle (thin filament organization) and non-muscle
      (cytoskeletal) isoforms, representing a core function of the gene.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments
    - reference_id: file:human/TPM3/TPM3-deep-research-falcon.md
      supporting_text: >-
        Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament
        identity, and thin-filament regulation in muscle.
- term:
    id: GO:0005884
    label: actin filament
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: TPM3 localizes to actin filaments as an integral component. Tropomyosins are
      coiled-coil proteins that bind along the length of actin filaments. UniProt confirms "Binds to
      actin filaments in muscle and non-muscle cells" [UniProt P06753]. In muscle, TPM3 is part of
      the thin filament; in non-muscle cells, it decorates cytoskeletal actin filaments. This
      localization is fundamental to tropomyosin function.
    action: ACCEPT
    reason: Actin filament is the correct cellular component for TPM3 localization. This is a core
      structural feature of tropomyosins - they bind along the entire length of actin filaments as
      coiled-coil dimers. The IBA annotation is phylogenetically well-supported across the
      tropomyosin family.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Binds to actin filaments in muscle and non-muscle cells
    - reference_id: file:human/TPM3/TPM3-deep-research-falcon.md
      supporting_text: >-
        Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament
        identity, and thin-filament regulation in muscle.
- term:
    id: GO:0006936
    label: muscle contraction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Muscle contraction is a function specific to TPM3 Isoform 1 (skeletal muscle isoform,
      285 AA). UniProt states TPM3 "Plays a central role, in association with the troponin complex,
      in the calcium dependent regulation of vertebrate striated muscle contraction" [UniProt
      P06753]. The cytoskeletal isoforms (TM30nm) do not participate in muscle contraction. TPM3
      Isoform 1 is expressed in slow-twitch (type I) skeletal muscle fibers. Disease mutations
      causing CMYO4A demonstrate the importance of this function.
    action: KEEP_AS_NON_CORE
    reason: Muscle contraction is valid for the skeletal muscle isoform (Isoform 1) but not for
      cytoskeletal isoforms (Isoform 2/TM30nm and others). Since this annotation applies to only a
      subset of isoforms expressed in specific tissues, it should be marked as non-core. The core
      function of TPM3 across all isoforms is actin filament binding and organization, while muscle
      contraction is tissue/isoform-specific.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Plays a central role, in association with the troponin complex, in the
        calcium dependent regulation of vertebrate striated muscle contraction
    - reference_id: PMID:3018581
      supporting_text: a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle
    - reference_id: file:human/TPM3/TPM3-deep-research-falcon.md
      supporting_text: >-
        Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament
        identity, and thin-filament regulation in muscle.
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This IEA annotation for "actin binding" is derived from UniProt keyword mapping. While
      technically correct, it is less specific than the IBA annotation for GO:0051015 "actin
      filament binding" which better captures the mechanism by which TPM3 binds actin (along the
      filament, not to monomeric actin).
    action: ACCEPT
    reason: While GO:0051015 "actin filament binding" is more specific and preferred, this broader
      "actin binding" annotation is not incorrect. TPM3 does bind actin (specifically filamentous
      actin). The IEA provides complementary support to the more specific IBA annotation. Both can
      coexist as the more specific term is appropriately annotated via IBA.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Binds to actin filaments in muscle and non-muscle cells
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation for cytoskeleton localization is derived from UniProt subcellular
      location mapping. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location [UniProt
      P06753]. While correct, more specific terms like "actin filament" (GO:0005884) or "stress
      fiber" (GO:0001725) better describe the actual localization of TPM3.
    action: ACCEPT
    reason: The cytoskeleton annotation is a valid but general cellular component term. TPM3 is
      indeed a cytoskeletal protein, associating with actin filaments in both muscle and non-muscle
      cells. The more specific IBA annotation to "actin filament" (GO:0005884) provides better
      granularity, but this broader term is not incorrect.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005862
    label: muscle thin filament tropomyosin
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This IEA annotation from ARBA machine learning correctly identifies TPM3 as a component
      of muscle thin filament tropomyosin. However, this applies specifically to Isoform 1 (skeletal
      muscle isoform). The cytoskeletal isoforms (TM30nm/Isoform 2) are not part of the muscle thin
      filament structure. PMID:3018581 and PMID:3418707 clearly describe the tissue-specific
      alternative splicing that produces distinct muscle and non-muscle isoforms.
    action: KEEP_AS_NON_CORE
    reason: This annotation is accurate for the muscle isoform (Isoform 1) but not for cytoskeletal
      isoforms. The muscle thin filament complex includes tropomyosin in association with troponin
      for calcium-regulated muscle contraction. Since this is isoform-specific, it represents a
      non-core function. The core localization applicable to all isoforms is "actin filament"
      (GO:0005884).
    supported_by:
    - reference_id: PMID:3418707
      supporting_text: In muscle, alternative splicing of this gene results in the expression of a
        1.3 kb mRNA encoding a 285 amino acid skeletal muscle alpha-tropomyosin
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Plays a central role, in association with the troponin complex, in the
        calcium dependent regulation of vertebrate striated muscle contraction
    - reference_id: file:human/TPM3/TPM3-deep-research-falcon.md
      supporting_text: >-
        Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament
        identity, and thin-filament regulation in muscle.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14743216
  review:
    summary: This IPI annotation is from a large-scale TNF-alpha/NF-kappa B signaling pathway
      mapping study (PMID:14743216). The generic "protein binding" term provides limited functional
      information about TPM3's specific interactions. TPM3 is known to interact with specific
      partners including TMOD1, TNNT1, and the troponin complex in muscle [UniProt P06753].
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" (GO:0005515) is uninformative for GO annotation purposes.
      While TPM3 clearly interacts with proteins (actin, troponin components, etc.), this generic
      term does not capture the functional nature of those interactions. More specific molecular
      function terms like "actin filament binding" (GO:0051015) are already annotated.
      High-throughput interactome studies often identify many interactions without functional
      validation.
    supported_by:
    - reference_id: PMID:14743216
      supporting_text: A physical and functional map of the human TNF-alpha/NF-kappa B signal
        transduction pathway
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  review:
    summary: This annotation from PMID:16189514 (large-scale human protein-protein interaction
      network mapping) uses the generic "protein binding" term. This is a high-throughput study that
      identified many interactions without specific functional characterization.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative and considered a bad practice for GO
      annotation. TPM3's specific protein interactions (actin filaments, troponin complex, TMOD1,
      TNNT1) are better captured by more specific terms. Large-scale interactome data should ideally
      be used to generate more specific interaction annotations.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: Towards a proteome-scale map of the human protein-protein interaction network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: This annotation from PMID:17353931 (large-scale mapping of human protein-protein
      interactions by mass spectrometry) uses the generic "protein binding" term from
      high-throughput interaction data.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative for GO annotation. While TPM3 clearly
      engages in multiple protein-protein interactions, more specific molecular function terms are
      preferred. High-throughput mass spectrometry interactome studies provide evidence for
      interactions but rarely characterize the functional nature of those interactions.
    supported_by:
    - reference_id: PMID:17353931
      supporting_text: Large-scale mapping of human protein-protein interactions by mass
        spectrometry
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21516116
  review:
    summary: This annotation from PMID:21516116 (next-generation sequencing for interactome
      datasets) uses the generic "protein binding" term from high-throughput interaction data.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. TPM3's functionally relevant interactions
      (with actin filaments, troponin complex components) are better captured by specific terms.
      Generic protein binding from large-scale interactome studies does not provide mechanistic
      insight.
    supported_by:
    - reference_id: PMID:21516116
      supporting_text: Next-generation sequencing to generate interactome datasets
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: This annotation from PMID:25416956 (proteome-scale map of the human interactome
      network) uses the generic "protein binding" term from high-throughput interaction data.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative for GO annotation. Large-scale interactome
      mapping studies identify many interactions but the generic term does not convey functional
      information about TPM3's specific binding partners or the nature of those interactions.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25910212
  review:
    summary: This annotation from PMID:25910212 (macromolecular interaction perturbations in genetic
      disorders) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. While this study examines disease-relevant
      interactions, the generic annotation does not capture the specific functional context of TPM3
      interactions.
    supported_by:
    - reference_id: PMID:25910212
      supporting_text: Widespread macromolecular interaction perturbations in human genetic
        disorders [interaction perturbation study]
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  review:
    summary: This annotation from PMID:25959826 (interaction proteomics of neurodegenerative disease
      proteins) uses the generic "protein binding" term from high-throughput interaction data.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. This study focused on neurodegenerative
      disease proteins and TPM3 may have been identified as an interaction partner. However, the
      generic annotation does not provide functional insight.
    supported_by:
    - reference_id: PMID:25959826
      supporting_text: Quantitative interaction proteomics of neurodegenerative disease proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27107012
  review:
    summary: This annotation from PMID:27107012 (Barcode Fusion Genetics pooled-matrix protein
      interaction screens) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. High-throughput screening methods identify
      many interactions but the generic term does not convey the functional significance of specific
      TPM3 interactions.
    supported_by:
    - reference_id: PMID:27107012
      supporting_text: Pooled-matrix protein interaction screens using Barcode Fusion Genetics
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29128334
  review:
    summary: This annotation from PMID:29128334 (mitochondrial protein interactions linked to
      neurodegeneration) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. While this study links mitochondrial
      interactions to neurodegeneration, the generic annotation does not provide functional insight
      into TPM3's role. TPM3's primary localization is cytoskeletal/actin filaments, not
      mitochondrial.
    supported_by:
    - reference_id: PMID:29128334
      supporting_text: A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration
        Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31515488
  review:
    summary: This annotation from PMID:31515488 (disruption of protein interactions by genetic
      variants) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. While this study examines how genetic
      variants disrupt protein interactions, the generic annotation does not provide functional
      insight into specific TPM3 interactions.
    supported_by:
    - reference_id: PMID:31515488
      supporting_text: Extensive disruption of protein interactions by genetic variants across the
        allele frequency spectrum in human populations
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: This annotation from PMID:32296183 (reference map of the human binary protein
      interactome) uses the generic "protein binding" term from high-throughput interaction data.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative for GO annotation. Reference interactome
      maps identify many binary interactions but the generic term does not convey functional
      significance.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: This annotation from PMID:32814053 (interactome mapping of neurodegenerative disease
      proteins) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. While this study focuses on
      neurodegeneration-related protein aggregation, the generic annotation does not specify the
      functional context of any TPM3 interactions identified.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
        and Uncovers Widespread Protein Aggregation in Affected Brains
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: This annotation from PMID:33961781 (dual proteome-scale networks for cell-specific
      interactome remodeling) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. While this study examines cell-specific
      interactome remodeling, the generic annotation does not convey functional information about
      TPM3 interactions.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of the human
        interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: This annotation from PMID:40205054 (multimodal cell maps for structural and functional
      genomics) uses the generic "protein binding" term.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. Large-scale multimodal cell mapping
      identifies interactions but the generic annotation does not provide functional insight into
      TPM3's role.
    supported_by:
    - reference_id: PMID:40205054
      supporting_text: Multimodal cell maps as a foundation for structural and functional genomics
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  review:
    summary: This HTP annotation for mitochondrial localization is from a high-confidence human
      mitochondrial proteome study (PMID:34800366). However, TPM3's established localization is to
      actin filaments in the cytoskeleton. UniProt lists "Cytoplasm, cytoskeleton" as the
      subcellular location. Mitochondrial association may reflect high-throughput detection
      artifacts or transient/minor localization rather than a core functional site.
    action: MARK_AS_OVER_ANNOTATED
    reason: TPM3 is primarily a cytoskeletal protein that binds to actin filaments. The
      mitochondrial localization identified in this high-throughput proteomics study may represent
      contamination, transient association, or a minor pool of protein. The primary functional
      localization of TPM3 is to actin filaments (muscle thin filaments or cytoskeletal actin), not
      mitochondria. This annotation should be viewed with caution.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35510366
  review:
    summary: >-
      PMID:35510366 supports a TPM3-TNNT1 interaction in a muscle thin-filament disease context, but the
      GO term used here is the generic protein binding term rather than a specific thin-filament or troponin/tropomyosin
      interaction term.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The interaction is biologically relevant, but GO:0005515 is too generic to accept as a useful TPM3
      molecular-function annotation. TPM3 already has specific actin filament binding and muscle thin-filament
      context annotations; this row should not be treated as core protein-binding function.
    supported_by:
    - reference_id: PMID:35510366
      supporting_text: complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Interacts with TNNT1
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700179
  review:
    summary: >-
      This Reactome row describes cytosolic signaling context for oncogenic ALK fusion proteins that can
      use TPM3 as an N-terminal fusion partner, not native TPM3 actin-filament localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep only as non-core fusion-protein/pathway context. Native TPM3 function is actin-filament binding
      and cytoskeletal/thin-filament regulation; the ALK fusion Reactome pathways should not be used as
      primary evidence for normal TPM3 localization.
    supported_by:
    - reference_id: Reactome:R-HSA-9700179
      supporting_text: In addition to NPM, fusions with ALK have also been identified with EML4
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9700181
  review:
    summary: >-
      This Reactome row describes cytosolic signaling context for oncogenic ALK fusion proteins that can
      use TPM3 as an N-terminal fusion partner, not native TPM3 actin-filament localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep only as non-core fusion-protein/pathway context. Native TPM3 function is actin-filament binding
      and cytoskeletal/thin-filament regulation; the ALK fusion Reactome pathways should not be used as
      primary evidence for normal TPM3 localization.
    supported_by:
    - reference_id: Reactome:R-HSA-9700181
      supporting_text: After partner protein-mediated dimerization, ALK fusions are
        trans-autophosphorylated by the ALK kinase domain
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23892143
  review:
    summary: This annotation from PMID:23892143 (RSV N, P and M protein interactions in HEK-293T
      cells) uses the generic "protein binding" term. This study focused on respiratory syncytial
      virus protein interactions, and TPM3 may have been identified as a cellular interaction
      partner.
    action: MARK_AS_OVER_ANNOTATED
    reason: The term "protein binding" is uninformative. This study examined viral protein
      interactions and any TPM3 interactions identified likely represent host-pathogen interactions
      rather than TPM3's core cellular function. The generic annotation provides no functional
      insight.
    supported_by:
    - reference_id: PMID:23892143
      supporting_text: Human respiratory syncytial virus N, P and M protein interactions in HEK-293T
        cells
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  review:
    summary: This HDA annotation for extracellular exosome localization derives from PMID:20458337,
      a study of MHC class II-associated proteins in B-cell exosomes. The study "identified 539
      proteins" in exosomes from B cells. TPM3 detection in exosomes likely represents packaging of
      cytoskeletal components into exosomal cargo rather than a core functional localization.
    action: KEEP_AS_NON_CORE
    reason: Detection of TPM3 in extracellular exosomes represents exosomal cargo packaging rather
      than a site of TPM3 function. Cytoskeletal proteins are commonly found in exosome proteomes.
      This is a valid observation but does not represent a core functional localization for TPM3,
      which primarily functions on actin filaments in the cytoskeleton.
    supported_by:
    - reference_id: PMID:20458337
      supporting_text: we first analyzed the total proteome of highly purified B cell-derived
        exosomes using sensitive and accurate mass spectrometry (MS), and identified 539 proteins
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390593
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: Reactome:R-HSA-390593
      supporting_text: The cleft closes like a clam shell around the ATP molecule, triggering a
        large shape change that causes the myosin head to release actin
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390595
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Plays a central role, in association with the troponin complex, in the
        calcium dependent regulation of vertebrate striated muscle contraction
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390597
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Plays a central role, in association with the troponin complex, in the
        calcium dependent regulation of vertebrate striated muscle contraction
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-390598
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Plays a central role, in association with the troponin complex, in the
        calcium dependent regulation of vertebrate striated muscle contraction
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445699
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Smooth muscle contraction is regulated by interaction with caldesmon
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445700
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Smooth muscle contraction is regulated by interaction with caldesmon
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445704
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Smooth muscle contraction is regulated by interaction with caldesmon
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-445705
  review:
    summary: >-
      This cytosol annotation derives from a Reactome muscle contraction pathway step. It is compatible
      with TPM3-containing thin-filament complexes but is less informative than actin filament, muscle
      thin filament tropomyosin, or cytoskeleton localization.
    action: KEEP_AS_NON_CORE
    reason: >-
      Keep cytosol as non-core pathway context because TPM3 is a cytoskeletal/thin-filament actin-binding
      protein. The specific functional locations are actin filament, muscle thin filament tropomyosin,
      cytoskeleton, and, where directly supported, stress-fiber/cytoskeletal structures.
    supported_by:
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Smooth muscle contraction is regulated by interaction with caldesmon
- term:
    id: GO:0001725
    label: stress fiber
  evidence_type: IDA
  original_reference_id: PMID:16236705
  review:
    summary: >-
      Stress fiber localization is plausible for non-muscle cytoskeletal TPM3 isoforms, but the cached
      PMID:16236705 abstract supports h2-calponin effects on actin cytoskeleton rather than direct TPM3
      stress-fiber localization.
    action: UNDECIDED
    reason: >-
      The available cached evidence does not directly establish TPM3 localization to stress fibers. This
      annotation should remain undecided unless the full text or GO source confirms that TPM3 itself was
      assayed in stress fibers, or a direct TPM3 localization source is added.
    supported_by:
    - reference_id: PMID:16236705
      supporting_text: >-
        Force-expression of h2-calponin enhanced the resistance of the actin filaments to cytochalasin
        B treatment
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: >-
        In non-muscle cells is implicated in stabilizing cytoskeleton actin filaments
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: TAS
  original_reference_id: PMID:16130169
  review:
    summary: This TAS annotation for cytoskeleton localization derives from PMID:16130169, a
      proteomics study of HUVECs during etoposide-induced apoptosis. The study identified
      tropomyosin among proteins varying during apoptosis, indicating cytoskeletal involvement. The
      study confirmed "cellular functions more related to cell motility" among identified proteins.
    action: ACCEPT
    reason: The cytoskeleton annotation is correct for TPM3, which is established as a cytoskeletal
      protein. UniProt lists "Cytoplasm, cytoskeleton" as the subcellular location. While more
      specific terms (actin filament, stress fiber) exist, this general term is acceptable.
    supported_by:
    - reference_id: PMID:16130169
      supporting_text: illustrates various cellular functions more related to cell motility and
        angiogenesis
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton'
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: NAS
  original_reference_id: PMID:3418707
  review:
    summary: This NAS annotation for cytoskeleton derives from PMID:3418707, the foundational paper
      on hTMnm gene organization. The study characterized the gene producing both muscle and
      non-muscle (cytoskeletal) tropomyosin isoforms, clearly establishing TPM3's role in
      cytoskeletal function. The paper describes "TM30nm, a 248 amino acid cytoskeletal tropomyosin"
      in non-muscle cells.
    action: ACCEPT
    reason: This annotation directly refers to TPM3's cytoskeletal function as established in the
      original characterization of the gene. The paper explicitly describes the cytoskeletal isoform
      TM30nm. This is a core localization for the non-muscle isoforms of TPM3.
    supported_by:
    - reference_id: PMID:3418707
      supporting_text: In non-muscle tissue this gene produces a 2.5 kb (1 kb = 10(3) bases or
        base-pairs) mRNA encoding TM30nm, a 248 amino acid cytoskeletal tropomyosin
- term:
    id: GO:0005862
    label: muscle thin filament tropomyosin
  evidence_type: TAS
  original_reference_id: PMID:3018581
  review:
    summary: This TAS annotation for muscle thin filament tropomyosin derives from PMID:3018581,
      which characterized the tissue-specific expression of the TPM3 gene. The paper describes that
      in skeletal muscle, the gene produces "a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin"
      which functions as part of the muscle thin filament.
    action: KEEP_AS_NON_CORE
    reason: This annotation is accurate for the skeletal muscle isoform (Isoform 1, 285 AA) but not
      for the cytoskeletal isoforms. The muscle thin filament tropomyosin complex is specific to
      muscle tissue where TPM3 Isoform 1 functions with the troponin complex for calcium-regulated
      contraction. Since this is isoform-specific, it represents a non-core localization. The core
      localization applicable to all isoforms is "actin filament" (GO:0005884).
    supported_by:
    - reference_id: PMID:3018581
      supporting_text: a 1.3-kb mRNA encoding a 285-amino-acid tropomyosin in human skeletal muscle
    - reference_id: file:human/TPM3/TPM3-uniprot.txt
      supporting_text: Plays a central role, in association with the troponin complex, in the
        calcium dependent regulation of vertebrate striated muscle contraction
    - reference_id: file:human/TPM3/TPM3-deep-research-falcon.md
      supporting_text: >-
        Falcon report emphasizes TPM3 actin-filament binding/stabilization, isoform-specific actin filament
        identity, and thin-filament regulation in muscle.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:14743216
  title: A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction
    pathway.
  findings: []
- id: PMID:16130169
  title: Proteomics of human umbilical vein endothelial cells applied to etoposide-induced
    apoptosis.
  findings: []
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
- id: PMID:16236705
  title: h2-Calponin is regulated by mechanical tension and modifies the function of actin
    cytoskeleton.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications
    for exosome biogenesis.
  findings: []
- id: PMID:21516116
  title: Next-generation sequencing to generate interactome datasets.
  findings: []
- id: PMID:23892143
  title: Human respiratory syncytial virus N, P and M protein interactions in HEK-293T cells.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:25910212
  title: Widespread macromolecular interaction perturbations in human genetic disorders.
  findings: []
- id: PMID:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
- id: PMID:27107012
  title: Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
  findings: []
- id: PMID:29128334
  title: A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New
    Mechanisms of Redox Homeostasis and NF-κB Signaling.
  findings: []
- id: PMID:3018581
  title: Tissue-specific expression of the human tropomyosin gene involved in the generation of the
    trk oncogene.
  findings: []
- id: PMID:31515488
  title: Extensive disruption of protein interactions by genetic variants across the allele
    frequency spectrum in human populations.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers
    Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:3418707
  title: Organization of the hTMnm gene. Implications for the evolution of muscle and non-muscle
    tropomyosins.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular
    context.
  findings: []
- id: PMID:35510366
  title: Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-390593
  title: ATP Hydrolysis By Myosin
  findings: []
- id: Reactome:R-HSA-390595
  title: Calcium Binds Troponin-C
  findings: []
- id: Reactome:R-HSA-390597
  title: Release Of ADP From Myosin
  findings: []
- id: Reactome:R-HSA-390598
  title: Myosin Binds ATP
  findings: []
- id: Reactome:R-HSA-445699
  title: ATP Hydrolysis By Myosin
  findings: []
- id: Reactome:R-HSA-445700
  title: Myosin Binds ATP
  findings: []
- id: Reactome:R-HSA-445704
  title: Calcium Binds Caldesmon
  findings: []
- id: Reactome:R-HSA-445705
  title: Release Of ADP From Myosin
  findings: []
- id: Reactome:R-HSA-9700179
  title: Ligand-independent dimerization of ALK fusions
  findings: []
- id: Reactome:R-HSA-9700181
  title: Autophosphorylation of ALK fusions
  findings: []
- id: file:human/TPM3/TPM3-deep-research-falcon.md
  title: Falcon deep research on TPM3 function
  findings:
  - statement: TPM3 is an actin-filament binding coiled-coil tropomyosin whose isoforms stabilize
      and regulate distinct actin filament populations.
    supporting_text: >-
      Falcon report summarizes TPM3 as an actin-binding coiled-coil dimer that polymerizes along F-actin
      to stabilize filaments and regulate access of myosin and other actin-binding proteins.
- id: file:human/TPM3/TPM3-uniprot.txt
  title: UniProt record for human TPM3
  findings: []
core_functions:
- molecular_function:
    id: GO:0051015
    label: actin filament binding
  description: Actin filament binding is the fundamental molecular function of all TPM3 isoforms.
    Tropomyosins are coiled-coil proteins that bind along the length of actin filaments in both
    muscle and non-muscle cells. UniProt states "Binds to actin filaments in muscle and non-muscle
    cells" [UniProt P06753]. This function is conserved across the tropomyosin family (IBA evidence)
    and is essential for TPM3's roles in muscle contraction regulation and cytoskeletal
    stabilization.
  directly_involved_in:
  - id: GO:0007015
    label: actin filament organization
  locations:
  - id: GO:0005884
    label: actin filament
  supported_by:
  - reference_id: file:human/TPM3/TPM3-deep-research-falcon.md
    supporting_text: >-
      Falcon report summarizes TPM3 as binding and stabilizing F-actin and regulating actin interactions
      with myosin and other actin-binding proteins.
alternative_products:
- name: 1 (Skeletal muscle)
  id: P06753-1
  description: >-
    The skeletal muscle isoform specific to slow-twitch (type I) muscle fibers. Regulates
    actin-myosin interaction during muscle contraction in slow oxidative fibers. Mutations
    cause nemaline myopathy and congenital fiber type disproportion. GO annotations
    for
    "muscle contraction" apply to this isoform but NOT to the cytoskeletal isoform
    2.
- name: 2 (Cytoskeletal, TM30nm)
  id: P06753-2
  sequence_note: VSP_006604, VSP_006605, VSP_006606
  description: >-
    The cytoskeletal/non-muscle isoform, also called TM30nm or gamma-tropomyosin.
    Functions
    in non-muscle cells for actin cytoskeleton organization, cell motility, and cytokinesis.
    Has DISTINCT functions from the muscle isoform - GO annotations for "muscle contraction"
    do NOT apply to this isoform.
- name: '3'
  id: P06753-3
  sequence_note: VSP_006604, VSP_006605, VSP_006607
  description: >-
    A cytoskeletal-related isoform. Similar to isoform 2 in having non-muscle functions.
- name: '4'
  id: P06753-4
  sequence_note: VSP_047302, VSP_047303, VSP_047304,
  description: >-
    A less characterized isoform. Functional role not well established in the literature.
- name: '5'
  id: P06753-5
  sequence_note: VSP_047302, VSP_047303, VSP_047304,
  description: >-
    A less characterized isoform. Functional role not well established in the literature.
- name: '6'
  id: P06753-6
  sequence_note: VSP_006604, VSP_006605
  description: >-
    A less characterized isoform. Likely has cytoskeletal functions based on exon
    usage.
- name: '7'
  id: P06753-7
  sequence_note: VSP_054792, VSP_006606
  description: >-
    A less characterized isoform. Functional role not well established in the literature.
proposed_new_terms: []
suggested_questions:
- question: Which TPM3 isoforms should receive isoform-specific GO annotation for muscle contraction
    versus non-muscle actin cytoskeleton organization?
  experts:
  - GO isoform annotation curators
  - muscle biologists
- question: Which high-throughput TPM3 protein-binding annotations correspond to functional
    actin/thin-filament biology rather than nonspecific interactome detections?
  experts:
  - protein interaction curators
  - cytoskeleton specialists
suggested_experiments:
- experiment_type: Isoform-specific actin filament assay
  description: Compare major TPM3 isoforms for F-actin binding, filament stabilization, myosin
    regulation, and protection from cofilin/gelsolin-mediated disassembly.
  hypothesis: Distinct TPM3 isoforms specify actin filament populations with different mechanical
    and regulatory properties.
- experiment_type: Endogenous isoform mapping
  description: Use long-read transcriptomics and targeted proteomics in slow skeletal muscle and
    non-muscle cells to map TPM3 isoform expression to GO-relevant functions.
  hypothesis: Muscle contraction annotations map mainly to skeletal muscle isoform 1, whereas
    cytoskeletal organization annotations map to shorter non-muscle isoforms.

TPM3

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Research report: Human TPM3 (UniProt P06753) — functional annotation, mechanisms, and current clinical relevance

Executive summary

Identity verification (mandatory)

1) Key concepts and definitions (current understanding)

1.1 Tropomyosin / TPM3 as an actin-filament “regulatory coat”

1.2 Isoforms and isoform logic

2) Localization, expression, and pathway/complex context

2.1 Subcellular localization

2.2 Tissue and fiber-type expression

2.3 Pathways and complexes

3) Recent developments and latest research (prioritizing 2023–2024)

3.1 Mechanistic refinement: isoform-specific outputs on actin/myosin

3.2 Myopathy mechanisms: actin affinity and structural instability

3.3 Precision oncology: TPM3 as a recurrent fusion partner

4) Applications and real-world implementations

4.1 Diagnostics: detection of TPM3 rearrangements

4.2 Therapeutics: TRK inhibitors in NTRK-fusion cancers (including TPM3::NTRK1)

5) Statistics and quantitative data from recent sources

5.1 TPM3 gene and isoform quantitative descriptors

5.2 Muscle fiber-type expression statistic

5.3 NTRK fusion frequencies and TPM3::NTRK1 context

5.4 Real-world TRK inhibitor outcomes (pediatric cohort)

5.5 Pharmacovigilance statistics for TRK inhibitors

Expert interpretation and synthesis

Embedded structured summary

Key visual evidence (from 2024 review)

Primary sources cited (URLs; publication dates)

Citations

Notes

TPM3 (Tropomyosin 3) Notes - ISOFORMS Project

Key Isoform Biology

Tissue-Specific Isoforms

Functional Distinctions

Disease Associations

Relationship to TPM1

Expected Annotation Issues

GOA Annotation Count: 39

📄 View Raw YAML