Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0031012 extracellular matrix	IBA GO_REF:0000033	ACCEPT	Summary: Testican-1 is a secreted proteoglycan that localizes to and is a structural component of the extracellular matrix. Multiple lines of evidence support this core localization. Reason: IBA annotation is well-supported by experimental evidence. UniProt states "Secreted, extracellular space, extracellular matrix". Multiple proteomics studies (PMID:27068509, PMID:32055794, PMID:33266304) identified testican-1 in ECM preparations using HDA evidence. The protein is described as an ECM proteoglycan in the original characterization (PMID:8389704). This is a core function of testican-1. Supporting Evidence: PMID:8389704 The molecular characterization of a human testicular proteoglycan, the progenitor of a seminal plasma glycosaminoglycan-bearing peptide, was achieved by cDNA cloning. file:human/SPOCK1/SPOCK1-uniprot.txt SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular matrix. file:human/SPOCK1/SPOCK1-deep-research-falcon.md model: Edison Scientific Literature
GO:0008191 metalloendopeptidase inhibitor activity	IBA GO_REF:0000033	ACCEPT	Summary: Testican-1 directly inhibits membrane-type matrix metalloproteinases (MT-MMPs) including MT1-MMP and MT3-MMP, preventing pro-MMP-2 activation. This is a core molecular function. Reason: IBA annotation is supported by experimental evidence from PMID:11751414 showing direct interaction with MT1-MMP and MT3-MMP and inhibition of pro-MMP-2 activation. While this study focused on testican-3, it explicitly states "Expression of testican 1 or testican 3 but not testican 2 also inhibited pro-MMP-2 activation". This metalloproteinase inhibitor activity is a core function of testican-1. Supporting Evidence: PMID:11751414 Expression of testican 1 or testican 3 but not testican 2 also inhibited pro-MMP-2 activation by either MT1-MMP or MT3-MMP.
GO:0010810 regulation of cell-substrate adhesion	IBA GO_REF:0000033	ACCEPT	Summary: Testican-1 regulates cell-substrate adhesion, with experimental evidence showing it inhibits Neuro-2a cell attachment. The IBA term appropriately captures this regulatory function. Reason: IBA annotation is supported by experimental evidence from PMID:12853036 and PMID:8389704. The protein is explicitly described as resembling "modulators of cell social behaviour" and experimental data shows it inhibits neuron attachment (PMID:12853036). This is a core function related to ECM-mediated cell adhesion modulation. Supporting Evidence: PMID:8389704 Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour. PMID:12853036 We demonstrate that testican inhibits attachment of Neuro-2a cells and their ability to form neurite extensions.
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: Testican-1 is secreted to the extracellular space as confirmed by UniProt and experimental detection in extracellular fluids. Reason: IBA annotation is consistent with the protein being secreted (signal peptide residues 1-21) and detected in extracellular locations including seminal plasma and as part of the ECM. This is a core localization. Supporting Evidence: file:human/SPOCK1/SPOCK1-uniprot.txt SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular matrix. PMID:14511383 Testican-1, a secreted proteoglycan enriched in brain
GO:0005509 calcium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: Testican-1 contains extracellular calcium-binding (EC) domains similar to those in BM-40/SPARC. Direct experimental evidence confirms calcium binding activity. Reason: IBA annotation is supported by both sequence analysis (InterPro IPR019577 SPARC/Testican Ca-binding domain) and experimental evidence from PMID:9323035 demonstrating calcium binding with Kd=68 microM. The EC domain shows structural changes upon calcium depletion. This is a core molecular function. Supporting Evidence: PMID:9323035 The extracellular calcium-binding (EC) module of human testican (115 residues) was obtained in native form by recombinant production in mammalian cell culture and thus shown to represent an independently folding domain. This module showed a large loss in alpha-helix upon calcium depletion. Apparently only one of the two EF hands binds calcium, with a moderate affinity (Kd =68 microM)
GO:0005509 calcium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate IEA annotation based on InterPro domain IPR019577. Redundant with IBA and IDA evidence for same term. Reason: This IEA annotation is based on the presence of the SPARC/Testican calcium-binding domain (InterPro IPR019577) and is consistent with experimental evidence. While duplicate, it provides computational confirmation of the calcium-binding function. Supporting Evidence: file:human/SPOCK1/SPOCK1-uniprot.txt InterPro: IPR019577; SPARC/Testican_Ca-bd-dom
GO:0008191 metalloendopeptidase inhibitor activity	IEA GO_REF:0000117	ACCEPT	Summary: Duplicate IEA annotation from ARBA machine learning. Redundant with IBA and IDA evidence for same term. Reason: This IEA annotation provides computational support for the metalloendopeptidase inhibitor activity that is experimentally validated by IBA and IDA evidence. Acceptable as supporting evidence. Supporting Evidence: GO_REF:0000117 Electronic annotation by ARBA machine learning models
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: Generic protein binding annotation from binary interactome study. Too vague to be informative about testican-1 function. Reason: The term "protein binding" provides no functional information about testican-1's specific role. While the protein does bind to other proteins (MT-MMPs, cathepsin L, etc.), these interactions are better captured by more specific terms like metalloendopeptidase inhibitor activity and cysteine-type endopeptidase inhibitor activity. PMID:32296183 is a high-throughput interactome study that does not provide specific functional context. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome
GO:0005201 extracellular matrix structural constituent	HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper...	ACCEPT	Summary: Testican-1 functions as a structural component of the ECM, identified in matrisome proteomics studies. This is a core molecular function. Reason: HDA annotation from ECM proteomics study is appropriate. As a proteoglycan with GAG chains that localizes to the ECM, testican-1 contributes to ECM structure. The modular domain architecture and proteoglycan nature support this structural role. Supporting Evidence: file:human/SPOCK1/SPOCK1-uniprot.txt O-glycosylated. Glycosaminoglycan that contains chondroitin sulfate and heparan sulfate. PMID:8389704 Testican is the progenitor of the unique heparan/chondroitin-sulfate-bearing peptide present in human seminal plasma PMID:27068509 Apr 11. Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.
GO:0031012 extracellular matrix	HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper...	ACCEPT	Summary: Duplicate HDA annotation for ECM localization from varicose vein ECM proteomics. Redundant with IBA annotation. Reason: This HDA annotation provides independent proteomics evidence for ECM localization from a study on extracellular matrix remodeling in human varicose veins. Multiple independent HDA studies confirm this core localization. Supporting Evidence: PMID:27068509 Apr 11. Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.
GO:0031012 extracellular matrix	HDA PMID:32055794 3D mapping of native extracellular matrix reveals cellular r...	ACCEPT	Summary: Duplicate HDA annotation for ECM localization from 3D ECM mapping study. Redundant with IBA and other HDA annotations. Reason: Additional proteomics evidence for ECM localization from independent study on 3D mapping of native extracellular matrix. Reinforces core localization. Supporting Evidence: PMID:32055794 3D mapping of native extracellular matrix reveals cellular responses to the microenvironment.
GO:0031012 extracellular matrix	HDA PMID:33266304 Divide-and-Conquer Matrisome Protein (DC-MaP) Strategy: An M...	ACCEPT	Summary: Duplicate HDA annotation for ECM localization from matrisome characterization study. Redundant with IBA and other HDA annotations. Reason: Additional proteomics evidence for ECM localization from Divide-and-Conquer Matrisome Protein (DC-MaP) strategy study. Multiple independent HDA studies provide strong support for this core localization. Supporting Evidence: PMID:33266304 Divide-and-Conquer Matrisome Protein (DC-MaP) Strategy: An MS-Friendly Approach to Proteomic Matrisome Characterization.
GO:0001558 regulation of cell growth	NAS PMID:8389704 Testican, a multidomain testicular proteoglycan resembling m...	KEEP AS NON CORE	Summary: Original paper describes testican-1 as resembling modulators of cell social behavior, but provides no direct experimental evidence for regulation of cell growth. Reason: The annotation is based on NAS (non-traceable author statement) from the original characterization paper. While the multidomain structure suggests potential roles in cell proliferation, this is not a core function based on current evidence. The primary characterized functions are ECM structural roles and protease inhibition. Supporting Evidence: PMID:8389704 Its protein core encompasses several domains encountered in various proteins associated with adhesion, migration and cell proliferation.
GO:0001764 neuron migration	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation based on orthology to mouse testican-1 (Q62288). While testican-1 affects neuron attachment, direct evidence for neuron migration is limited. Reason: ISS annotation transferred from mouse ortholog. While testican-1 clearly affects neuronal cell adhesion and neurite extension (PMID:12853036), migration is a distinct process. This is potentially valid but peripheral to the core ECM structural and protease inhibitor functions. Supporting Evidence: GO_REF:0000024 Manual transfer from mouse ortholog UniProtKB:Q62288
GO:0004867 serine-type endopeptidase inhibitor activity	NAS PMID:14511383 Human proteoglycan testican-1 inhibits the lysosomal cystein...	UNDECIDED	Summary: NAS annotation suggesting serine protease inhibitor activity based on Kazal-like domain presence, but experimental evidence in same paper focused on cysteine protease inhibition. Reason: Kazal-like domains are typically serine protease inhibitors, and testican-1 contains a Kazal-like domain (residues 130-182). However, PMID:14511383 experimentally demonstrated cysteine protease (cathepsin L) inhibition but did not test serine proteases. The NAS evidence is weak without direct experimental validation. Would need experimental testing to confirm. Supporting Evidence: file:human/SPOCK1/SPOCK1-uniprot.txt DOMAIN 130..182 Kazal-like PMID:14511383 Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin L.
GO:0004869 cysteine-type endopeptidase inhibitor activity	IDA PMID:14511383 Human proteoglycan testican-1 inhibits the lysosomal cystein...	ACCEPT	Summary: Direct experimental demonstration that testican-1 inhibits cathepsin L with Ki=0.7 nM via its thyroglobulin type-1 domain. This is a core molecular function. Reason: Strong IDA evidence from PMID:14511383 showing potent and specific inhibition of cathepsin L (Ki=0.7 nM) but not cathepsin B. The thyroglobulin domain mediates this activity. This is a well-characterized core function of testican-1. Supporting Evidence: PMID:14511383 We demonstrate that purified recombinant human testican-1 is a strong competitive inhibitor of the lysosomal cysteine protease, cathepsin L, with a Ki of 0.7 nM, but it does not inhibit the structurally related lysosomal cysteine protease cathepsin B.
GO:0005509 calcium ion binding	IDA PMID:9323035 Properties of the extracellular calcium binding module of th...	ACCEPT	Summary: Duplicate IDA annotation for calcium binding. Redundant with IBA annotation for same term, both supported by same experimental evidence. Reason: This IDA annotation provides direct experimental evidence for calcium binding (Kd=68 microM) and is the primary experimental reference. Consistent with IBA and IEA annotations for the same function. Supporting Evidence: PMID:9323035 Apparently only one of the two EF hands binds calcium, with a moderate affinity (Kd =68 microM)
GO:0005615 extracellular space	IDA PMID:14511383 Human proteoglycan testican-1 inhibits the lysosomal cystein...	ACCEPT	Summary: Duplicate IDA annotation for extracellular space localization. Redundant with IBA annotation. Reason: IDA evidence from purification and characterization of secreted testican-1 from cell culture medium. Supports IBA annotation for same localization. Supporting Evidence: PMID:14511383 Testican-1, a secreted proteoglycan enriched in brain
GO:0005737 cytoplasm	ISS GO_REF:0000024	REMOVE	Summary: ISS annotation based on mouse ortholog suggesting cytoplasmic localization. Inconsistent with primary secreted localization. Reason: Testican-1 has a signal peptide (residues 1-21) and is characterized as a secreted proteoglycan. UniProt annotation states "Secreted, extracellular space, extracellular matrix" with no mention of cytoplasmic localization. While the protein may transiently pass through the cytoplasm during secretion, cytoplasm is not a functional localization for this protein. This ISS annotation from mouse ortholog appears incorrect. Supporting Evidence: file:human/SPOCK1/SPOCK1-uniprot.txt SIGNAL 1..21; SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular matrix.
GO:0007155 cell adhesion	NAS PMID:8389704 Testican, a multidomain testicular proteoglycan resembling m...	ACCEPT	Summary: NAS annotation for cell adhesion based on structural similarity to cell adhesion modulators. Supported by experimental data on adhesion regulation. Reason: While NAS evidence is weak, the annotation is supported by the protein's domain structure and experimental evidence from PMID:12853036 showing regulation of cell attachment. This is appropriately a general cell adhesion term that encompasses the more specific regulation of cell-substrate adhesion function. Supporting Evidence: PMID:8389704 Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour. PMID:12853036 We demonstrate that testican inhibits attachment of Neuro-2a cells
GO:0007399 nervous system development	NAS PMID:9181134 [Cloning of testican/SPOCK in man and mouse. Neuromuscular e...	KEEP AS NON CORE	Summary: NAS annotation for nervous system development based on brain expression and postsynaptic localization. Testican-1 is enriched in brain. Reason: While testican-1 is highly expressed in brain and affects neuron attachment/neurite extension, nervous system development is a broad process term that may be peripheral to the core molecular functions (ECM structure, protease inhibition, adhesion modulation). The NAS evidence is weak but consistent with expression patterns. Supporting Evidence: PMID:9181134 Structural analysis, a main expression in nervous system and preliminary assignment of the human gene in a critical region for neuropathologies, suggest that SPOCK may be of importance in neural development
GO:0008191 metalloendopeptidase inhibitor activity	IDA PMID:11751414 Suppression of membrane-type 1 matrix metalloproteinase (MMP...	ACCEPT	Summary: Duplicate IDA annotation for metalloendopeptidase inhibitor activity. Redundant with IBA annotation. Reason: IDA annotation provides direct experimental evidence for MT-MMP inhibition. This is the primary experimental reference supporting the IBA annotation. Core molecular function. Supporting Evidence: PMID:11751414 Expression of testican 1 or testican 3 but not testican 2 also inhibited pro-MMP-2 activation by either MT1-MMP or MT3-MMP.
GO:0010812 negative regulation of cell-substrate adhesion	IDA PMID:12853036 Testican-1 inhibits attachment of Neuro-2a cells.	ACCEPT	Summary: Direct experimental evidence showing testican-1 inhibits Neuro-2a cell attachment to substrate. More specific than the IBA term for regulation of cell-substrate adhesion. Reason: Strong IDA evidence showing testican-1 inhibits cell attachment when coated on substrate, blocking attachment sites. This negative regulatory function is well-characterized and represents a core activity related to ECM-mediated adhesion modulation. Supporting Evidence: PMID:12853036 We demonstrate that testican inhibits attachment of Neuro-2a cells and their ability to form neurite extensions. Both testican proteoglycan and the core glycoprotein that has been depleted of chondroitin sulfate inhibit cell attachment. Pre-treatment of the culture substratum with testican inhibits Neuro-2a attachment
GO:0010977 negative regulation of neuron projection development	IDA PMID:12853036 Testican-1 inhibits attachment of Neuro-2a cells.	ACCEPT	Summary: Direct experimental evidence showing testican-1 inhibits neurite extension in Neuro-2a cells. Represents a specific neuronal function. Reason: Strong IDA evidence from PMID:12853036 demonstrating inhibition of neurite extensions. This is a well-characterized activity but may be considered non-core as it represents a tissue-specific manifestation of the broader adhesion modulation function. Supporting Evidence: PMID:12853036 We demonstrate that testican inhibits attachment of Neuro-2a cells and their ability to form neurite extensions.
GO:0014069 postsynaptic density	NAS PMID:9181134 [Cloning of testican/SPOCK in man and mouse. Neuromuscular e...	KEEP AS NON CORE	Summary: NAS annotation for postsynaptic density localization based on immunoelectron microscopy showing selective localization in postsynaptic densities. Reason: The annotation is based on immunoelectron microscopy data from PMID:9181134 showing localization to postsynaptic densities of pyramidal neurons and Purkinje cells. However, this is a specialized sub-localization within the broader CNS expression pattern and represents a non-core, tissue-specific localization. Supporting Evidence: PMID:9181134 Immunoelectron microscopy showed the antigen selectively localized in the post-synaptic density of scattered pyramidal neurons and Purkinje cells.
GO:0016528 sarcoplasm	ISS GO_REF:0000024	REMOVE	Summary: ISS annotation for sarcoplasm localization based on mouse ortholog. Inconsistent with secreted nature of protein. Reason: Similar to the cytoplasm annotation, sarcoplasm is inconsistent with testican-1 being a secreted ECM proteoglycan. This ISS annotation from mouse ortholog appears incorrect for a protein with a signal peptide that functions in the extracellular space. Supporting Evidence: file:human/SPOCK1/SPOCK1-uniprot.txt SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular matrix.
GO:0021953 central nervous system neuron differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for CNS neuron differentiation based on mouse ortholog. Represents a developmental process. Reason: ISS annotation from mouse ortholog. While testican-1 is highly expressed in brain and affects neuronal cell behavior, neuron differentiation is a broad developmental process that is peripheral to the core ECM structural and protease inhibitor functions. Supporting Evidence: GO_REF:0000024 Manual transfer from mouse ortholog
GO:0022008 neurogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for neurogenesis based on mouse ortholog. Very broad developmental process term. Reason: ISS annotation from mouse ortholog. Neurogenesis is an extremely broad process term. While testican-1 affects neuron behavior and is expressed in brain, this broad developmental process is peripheral to core functions. Supporting Evidence: GO_REF:0000024 Manual transfer from mouse ortholog
GO:0031594 neuromuscular junction	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for neuromuscular junction localization based on mouse ortholog. Specialized tissue-specific localization. Reason: ISS annotation from mouse ortholog suggesting localization to neuromuscular junctions. This is a specialized tissue-specific localization that is peripheral to the core ECM localization. May be valid but represents a minor sub-localization. Supporting Evidence: GO_REF:0000024 Manual transfer from mouse ortholog
GO:0033268 node of Ranvier	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS annotation for node of Ranvier localization based on mouse ortholog. Highly specialized neuronal structure. Reason: ISS annotation from mouse ortholog suggesting localization to nodes of Ranvier. This is a highly specialized sub-localization within myelinated axons that is peripheral to the core ECM function. May be valid but represents a minor tissue-specific localization. Supporting Evidence: GO_REF:0000024 Manual transfer from mouse ortholog
GO:0005518 collagen binding	IBA GO_REF:0000033	NEW	Summary: IBA annotation for collagen binding found in UniProt but not in GOA file. Testican-1 is an ECM proteoglycan that may interact with collagen. Reason: This IBA annotation appears in UniProt (DR GO; GO:0005518; F:collagen binding; IBA:GO_Central) but was not included in the GOA file provided. As an ECM proteoglycan, testican-1 may interact with collagen fibrils, though direct experimental evidence is lacking. PMID:9323035 tested the EC module for collagen binding and found "No clear evidence was obtained for collagen binding", suggesting this IBA annotation may be over-prediction. Requires experimental validation. Supporting Evidence: PMID:9323035 No clear evidence was obtained for collagen binding, indicating that EC modules found in different proteins may not share similar functions.
GO:0050840 extracellular matrix binding	IBA GO_REF:0000033	NEW	Summary: IBA annotation for ECM binding found in UniProt but not in GOA file. As an ECM proteoglycan, testican-1 likely interacts with ECM components. Reason: This IBA annotation appears in UniProt (DR GO; GO:0050840; F:extracellular matrix binding; IBA:GO_Central) but was not in the GOA file. As a proteoglycan with GAG chains that localizes to the ECM and modulates cell-matrix interactions, ECM binding is a reasonable function. However, specific binding partners beyond MT-MMPs have not been well characterized. This represents a core function consistent with the protein's role in ECM organization. Supporting Evidence: file:human/SPOCK1/SPOCK1-uniprot.txt May play a role in cell-cell and cell-matrix interactions.

Core Functions

Testican-1 functions as a structural component of the extracellular matrix, contributing to ECM organization through its proteoglycan nature with chondroitin sulfate and heparan sulfate GAG chains. Identified in multiple ECM proteomics studies.

Molecular Function:

extracellular matrix structural constituent

Cellular Locations:

extracellular matrix extracellular region

Supporting Evidence:

PMID:8389704
Testican is the progenitor of the unique heparan/chondroitin-sulfate-bearing peptide present in human seminal plasma
PMID:27068509
METHODS AND RESULTS: To understand the consequences of venous hypertension, normal and varicose veins were evaluated using proteomics approaches targeting the extracellular matrix
file:human/SPOCK1/SPOCK1-uniprot.txt
O-glycosylated. Glycosaminoglycan that contains chondroitin sulfate and heparan sulfate.

Testican-1 directly inhibits membrane-type matrix metalloproteinases (MT1-MMP and MT3-MMP), preventing pro-MMP-2 activation through direct protein-protein interaction.

Molecular Function:

metalloendopeptidase inhibitor activity

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:11751414
Expression of testican 1 or testican 3 but not testican 2 also inhibited pro-MMP-2 activation by either MT1-MMP or MT3-MMP.

Testican-1 is a potent competitive inhibitor of cathepsin L (Ki=0.7 nM) via its thyroglobulin type-1 domain. Does not inhibit cathepsin B. Active at both pH 5.5 and pH 7.2, functioning in both intracellular vesicles and extracellular space.

Molecular Function:

cysteine-type endopeptidase inhibitor activity

Cellular Locations:

extracellular region

Supporting Evidence:

PMID:14511383
We demonstrate that purified recombinant human testican-1 is a strong competitive inhibitor of the lysosomal cysteine protease, cathepsin L, with a Ki of 0.7 nM, but it does not inhibit the structurally related lysosomal cysteine protease cathepsin B.

The extracellular calcium-binding (EC) module contains EF-hand motifs and binds calcium with moderate affinity (Kd=68 microM). The module undergoes conformational change upon calcium binding.

Molecular Function:

calcium ion binding

Supporting Evidence:

PMID:9323035
Apparently only one of the two EF hands binds calcium, with a moderate affinity (Kd =68 microM)

Testican-1 binds to extracellular matrix components and modulates cell-matrix interactions, inhibiting neuron attachment to substrate and blocking neurite extension. This function is mediated by both the proteoglycan form and the core protein depleted of chondroitin sulfate.

Molecular Function:

extracellular matrix binding

Directly Involved In:

negative regulation of cell-substrate adhesion negative regulation of neuron projection development regulation of cell-substrate adhesion

Cellular Locations:

extracellular region extracellular matrix

Supporting Evidence:

PMID:12853036
We demonstrate that testican inhibits attachment of Neuro-2a cells and their ability to form neurite extensions. Both testican proteoglycan and the core glycoprotein that has been depleted of chondroitin sulfate inhibit cell attachment. Pre-treatment of the culture substratum with testican inhibits Neuro-2a attachment, but pre-treatment of the cells with testican does not inhibit their attachment. Testican, therefore, blocks attachment sites on cultureware and may also block attachment sites in the extracellular matrix of the brain.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms.

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:11751414

Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-Tes.

PMID:12853036

Testican-1 inhibits attachment of Neuro-2a cells.

PMID:14511383

Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin L.

PMID:27068509

Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.

PMID:32055794

3D mapping of native extracellular matrix reveals cellular responses to the microenvironment.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:33266304

Divide-and-Conquer Matrisome Protein (DC-MaP) Strategy: An MS-Friendly Approach to Proteomic Matrisome Characterization.

PMID:8389704

Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour.

PMID:9181134

[Cloning of testican/SPOCK in man and mouse. Neuromuscular expression perspectives in pathology].

PMID:9323035

Properties of the extracellular calcium binding module of the proteoglycan testican.

file:human/SPOCK1/SPOCK1-deep-research-falcon.md

Deep research report on SPOCK1

📚 Additional Documentation

Deep Research Falcon

(SPOCK1-deep-research-falcon.md)

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Precursor;'
gene_info: Name=SPOCK1; Synonyms=SPOCK, TIC1, TICN1;
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: EF-hand-dom_pair. (IPR011992); Kazal_dom. (IPR002350); Kazal_dom_sf.
(IPR036058); SPARC/Testican_Ca-bd-dom. (IPR019577); Thyroglobulin_1. (IPR000716)
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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: Q08629
Protein Description: RecName: Full=Testican-1; AltName: Full=Protein SPOCK; Flags: Precursor;
Gene Information: Name=SPOCK1; Synonyms=SPOCK, TIC1, TICN1;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: EF-hand-dom_pair. (IPR011992); Kazal_dom. (IPR002350); Kazal_dom_sf. (IPR036058); SPARC/Testican_Ca-bd-dom. (IPR019577); Thyroglobulin_1. (IPR000716)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SPOCK1" 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 'SPOCK1' 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 SPOCK1 (gene ID: SPOCK1, UniProt: Q08629) 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: Q08629
Protein Description: RecName: Full=Testican-1; AltName: Full=Protein SPOCK; Flags: Precursor;
Gene Information: Name=SPOCK1; Synonyms=SPOCK, TIC1, TICN1;
Organism (full): Homo sapiens (Human).
Protein Family: Not specified in UniProt
Key Domains: EF-hand-dom_pair. (IPR011992); Kazal_dom. (IPR002350); Kazal_dom_sf. (IPR036058); SPARC/Testican_Ca-bd-dom. (IPR019577); Thyroglobulin_1. (IPR000716)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "SPOCK1" 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 SPOCK1 (gene ID: SPOCK1, UniProt: Q08629) 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.

Comprehensive Research Report: Human SPOCK1 (Testican‑1) – Functional Annotation and Recent Evidence

Gene/protein verification and identity
- Symbol and accession: SPOCK1 encodes Testican‑1, a secreted extracellular matrix (ECM) proteoglycan in Homo sapiens. The SPOCK family (SPOCK1–3) are SPARC/osteonectin, CWCV and Kazal‑like domain proteoglycans with conserved modular architecture. SPOCK1 carries Ca2+‑binding EF‑hand motifs, a thyroglobulin type‑I (TY) domain, SPARC/Testican Ca‑binding regions, and C‑terminal glycosaminoglycan (GAG) attachment sites, matching the UniProt domain description provided (review, Oct 2024; https://doi.org/10.3892/mmr.2024.13355) (xiao2024spockmasterregulator pages 1-2, xiao2024spockmasterregulator pages 2-4, xiao2024spockmasterregulator pages 4-5).

1) Key concepts and definitions with current understanding
- Biochemical class and domains: Testican‑1/SPOCK1 is a secreted matricellular proteoglycan of the ECM bearing heparan/chondroitin sulfate GAG chains. Its domain architecture includes SPARC/osteonectin‑like modules, a thyroglobulin type I (TY) domain (with the characteristic CWCV motif), Kazal‑like region(s), and a Ca2+‑binding segment with EF‑hand motifs; two potential C‑terminal GAG attachment sites are present (review, 2024; https://doi.org/10.3892/mmr.2024.13355) (xiao2024spockmasterregulator pages 1-2, xiao2024spockmasterregulator pages 2-4, xiao2024spockmasterregulator pages 4-5).
- Core functions: SPOCK1 functions as a matricellular regulator of cell–matrix interactions and ECM remodeling. It modulates adhesion and neurite/axon growth in neural contexts and interacts with proteases; notably, testican‑1 can act as a potent competitive inhibitor of cathepsin L (CTSL) independent of its GAGs, and SPOCK family members regulate matrix metalloproteinases (MMPs), linking SPOCK1 to ECM proteolysis and epithelial–mesenchymal transition (EMT) in cancer (review, 2024; https://doi.org/10.3892/mmr.2024.13355) (xiao2024spockmasterregulator pages 2-4, xiao2024spockmasterregulator pages 4-5, xiao2024spockmasterregulator pages 1-2).
- Pathways and signaling: SPOCK1 has been repeatedly connected to pro‑tumor signaling programs including PI3K/AKT and Wnt/β‑catenin, and to EMT transcriptional programs; these links underpin invasion, metastasis and therapy response phenotypes in multiple cancers (review, 2024; https://doi.org/10.3892/mmr.2024.13355; LUAD study, Dec 2023; https://doi.org/10.1186/s12967-023-04616-3) (xiao2024spockmasterregulator pages 4-5, xiao2024spockmasterregulator pages 10-11, liu2023spock1asa pages 16-18).

2) Recent developments and latest research (prioritizing 2023–2024)
- SPOCK1 in lung adenocarcinoma (LUAD): A 2023 multi‑omics and experimental study identified SPOCK1 as upregulated in LUAD, associated with poor prognosis, EMT activation, and an immunosuppressive tumor microenvironment. SPOCK1 knockdown reduced invasion and migration in LUAD cells; connectivity‑map screening nominated VER‑155008, which reduced SPOCK1 expression and suppressed xenograft tumor growth, with stronger efficacy in SPOCK1‑high H1975 vs SPOCK1‑low H1299 models (Journal of Translational Medicine, Dec 2023; https://doi.org/10.1186/s12967-023-04616-3) (liu2023spock1asa pages 16-18, liu2023spock1asa pages 1-2).
- SPOCK1 and cancer‑associated fibroblasts (CAFs): LUAD cell–derived extracellular vesicles (EVs) and TGFβ independently activated fibroblasts; RNA‑seq identified SPOCK1 among the most upregulated ECM/EMT‑related genes across TGFβ and EV treatments. The study emphasized that SPOCK1 protein secretion from EV‑ or TGFβ‑activated CAFs was not demonstrated and warrants further validation (Biomedicines, Nov 2024; https://doi.org/10.3390/biomedicines12112523) (vazquez2024extracellularvesiclesfrom pages 80-85, vazquez2024extracellularvesiclesfrom pages 65-70, vazquez2024extracellularvesiclesfrom pages 85-89).
- SPOCK1 as a blood biomarker in stroke subtyping: A multicenter plasma proteomics study in the hyperacute window (≤6 h) reported that SPOCK1 distinguished intracerebral hemorrhage (ICH) from ischemic stroke (IS) with AUC ≈ 0.78–0.79, highlighting translational diagnostic potential (Biomarker Research, Oct 2025; https://doi.org/10.1186/s40364-025-00848-1) (nunezjurado2025plasmaproteomicsuncovers pages 11-14, nunezjurado2025plasmaproteomicsuncovers pages 14-15).

3) Current applications and real‑world implementations
- Oncology biomarker applications: In LUAD, high SPOCK1 identifies patients with worse overall survival, EMT activation, and immune suppression. Functionally, SPOCK1 knockdown reduces invasiveness, and small‑molecule modulation (VER‑155008) suppresses tumor growth preclinically, suggesting SPOCK1‑linked signatures as indicators for therapy sensitivity and as potential targets for intervention (J Transl Med, 2023; https://doi.org/10.1186/s12967-023-04616-3) (liu2023spock1asa pages 16-18).
- Tumor microenvironment/CAF biology: SPOCK1 is an EMT/ECM‑associated gene induced in fibroblasts by LUAD EVs and TGFβ, implicating it in CAF activation programs in lung cancer; protein‑level secretion into the milieu remains to be verified prior to clinical translation (Biomedicines, 2024; https://doi.org/10.3390/biomedicines12112523) (vazquez2024extracellularvesiclesfrom pages 80-85, vazquez2024extracellularvesiclesfrom pages 65-70, vazquez2024extracellularvesiclesfrom pages 85-89).
- Neurology diagnostics: Plasma SPOCK1 contributes to differentiating ICH from IS in the emergency setting with promising standalone AUCs, suggesting inclusion in multi‑analyte blood panels under development (Biomarker Research, 2025; https://doi.org/10.1186/s40364-025-00848-1) (nunezjurado2025plasmaproteomicsuncovers pages 11-14, nunezjurado2025plasmaproteomicsuncovers pages 14-15).

4) Expert opinions and analysis from authoritative sources
- Structural/functional consensus: An expert review in 2024 outlines SPOCK1 as a multi‑domain, ECM‑associated, calcium‑binding proteoglycan whose family regulates MMP activity and EMT, with emerging roles in PI3K/AKT and Wnt/β‑catenin signaling. The review underscores the need for mechanistic dissection and clinical validation to translate SPOCKs into reliable prognostic and therapeutic tools (Molecular Medicine Reports, Oct 2024; https://doi.org/10.3892/mmr.2024.13355) (xiao2024spockmasterregulator pages 1-2, xiao2024spockmasterregulator pages 4-5, xiao2024spockmasterregulator pages 10-11, xiao2024spockmasterregulator pages 9-10).
- LUAD translational perspective: Integrative analyses plus cell/xenograft validation position SPOCK1 as a biomarker of EMT and immune evasion and as a candidate therapeutic vulnerability; drug‑screening results offer a pragmatic route for repurposing strategies (Journal of Translational Medicine, Dec 2023; https://doi.org/10.1186/s12967-023-04616-3) (liu2023spock1asa pages 16-18).

5) Relevant statistics and data from recent studies
- LUAD prognosis/biology: High SPOCK1 expression correlates with shorter overall survival and lower CD8+ T‑cell infiltration; SPOCK1 knockdown suppresses invasion/migration and EMT markers. VER‑155008 reduced SPOCK1 and inhibited tumor growth with greater efficacy in SPOCK1‑high LUAD models; the study also reported differential chemotherapeutic sensitivity associations by SPOCK1 level (Journal of Translational Medicine, Dec 2023; https://doi.org/10.1186/s12967-023-04616-3) (liu2023spock1asa pages 16-18).
- Stroke diagnostic performance: SPOCK1 showed ICH vs IS discrimination with AUCs ≈ 0.782–0.786 in a multicenter cohort sampled ≤6 h from onset, with reported sensitivity 68.2% and specificity 79.9% in one analysis; authors propose SPOCK1 as a component of blood‑based panels for hyperacute stroke triage (Biomarker Research, Oct 2025; https://doi.org/10.1186/s40364-025-00848-1) (nunezjurado2025plasmaproteomicsuncovers pages 11-14, nunezjurado2025plasmaproteomicsuncovers pages 14-15).
- CAF activation: SPOCK1 was among the most upregulated EMT/ECM genes in fibroblasts exposed to LUAD EVs or TGFβ across RNA‑seq comparisons; secretion from CAFs was not confirmed and requires further experiments (Biomedicines, Nov 2024; https://doi.org/10.3390/biomedicines12112523) (vazquez2024extracellularvesiclesfrom pages 80-85, vazquez2024extracellularvesiclesfrom pages 65-70, vazquez2024extracellularvesiclesfrom pages 85-89).
- Therapy resistance mechanics (supplemental, 2025): An Oncogene study identified an RBM15→m6A‑dependent epigenetic silencing of SPOCK1 that contributes to EMT‑associated osimertinib resistance in LUAD. RBM15 knockdown increased SPOCK1 and restored osimertinib sensitivity (IC50 drop from 6.404 μM to 3.439 μM), while concurrent SPOCK1 knockdown reversed this sensitization and EMT marker reversion, positioning the RBM15–SPOCK1 axis as a resistance node (Oncogene, Nov 2025; https://doi.org/10.1038/s41388-024-03220-z) (li2025rbm15facilitatesosimertinib pages 7-9).

Function, pathways, and localization: consolidated view
- Primary function: SPOCK1/Testican‑1 is a secreted ECM proteoglycan with calcium‑binding and protease‑interacting domains; it modulates ECM remodeling by regulating proteases (e.g., MMP axis contextually; cathepsin L inhibition demonstrated) and functions as a matricellular cue influencing adhesion, neurite outgrowth, EMT and invasion programs (review, 2024; https://doi.org/10.3892/mmr.2024.13355; LUAD, 2023; https://doi.org/10.1186/s12967-023-04616-3) (xiao2024spockmasterregulator pages 2-4, xiao2024spockmasterregulator pages 4-5, xiao2024spockmasterregulator pages 1-2, liu2023spock1asa pages 16-18).
- Cellular/tissue localization: SPOCK1 is secreted to the ECM, enriched at basement‑membrane‑like structures and neural tissues. The highest physiologic expression is in the human brain, with expression also reported in other organs; tumor contexts show stromal/CAF involvement and cancer‑cell upregulation (review, 2024; https://doi.org/10.3892/mmr.2024.13355; Biomedicines, 2024; https://doi.org/10.3390/biomedicines12112523; J Transl Med, 2023; https://doi.org/10.1186/s12967-023-04616-3) (xiao2024spockmasterregulator pages 2-4, xiao2024spockmasterregulator pages 1-2, vazquez2024extracellularvesiclesfrom pages 80-85, liu2023spock1asa pages 16-18).
- Pathways: SPOCK1 promotes EMT and invasive phenotypes via PI3K/AKT and Wnt/β‑catenin signaling in cancer models; in LUAD, high SPOCK1 aligns with EMT activation and immune evasion. TGFβ stimulation can induce SPOCK1 expression in tumor contexts and in fibroblasts; LUAD EVs likewise induce SPOCK1 mRNA in fibroblasts, implicating intercellular communication in TME remodeling (review, 2024; https://doi.org/10.3892/mmr.2024.13355; J Transl Med, 2023; https://doi.org/10.1186/s12967-023-04616-3; Biomedicines, 2024; https://doi.org/10.3390/biomedicines12112523) (xiao2024spockmasterregulator pages 4-5, xiao2024spockmasterregulator pages 10-11, liu2023spock1asa pages 16-18, vazquez2024extracellularvesiclesfrom pages 80-85, vazquez2024extracellularvesiclesfrom pages 65-70, vazquez2024extracellularvesiclesfrom pages 85-89).
- Immune contexture: In LUAD, higher SPOCK1 correlates with a more immunosuppressive TME and reduced CD8+ T‑cell infiltration, consistent with EMT‑linked immune exclusion; these findings support SPOCK1 as a biomarker of immune evasion (J Transl Med, 2023; https://doi.org/10.1186/s12967-023-04616-3) (liu2023spock1asa pages 16-18).

Notes on gene symbol ambiguity
- The SPOCK1 symbol here refers to human Testican‑1. The organism (Homo sapiens) and the domain architecture we describe align with the UniProt Q08629 entry and with the 2024 SPOCK family review, ensuring we are analyzing the correct gene/protein (review, 2024; https://doi.org/10.3892/mmr.2024.13355) (xiao2024spockmasterregulator pages 1-2, xiao2024spockmasterregulator pages 2-4).

Evidence gaps and open questions
- Quantitative prognostic statistics (e.g., hazard ratios) for SPOCK1 in LUAD were not reported in the 2023 study excerpts here; however, directional associations (worse survival with higher SPOCK1) are supported alongside functional validations and a drug‑repurposing hit. Additional cohort‑level HRs would further strengthen prognostic claims (J Transl Med, 2023; https://doi.org/10.1186/s12967-023-04616-3) (liu2023spock1asa pages 16-18).
- CAF secretion of SPOCK1 protein following EV/TGFβ activation was not demonstrated in the 2024 LUAD EV study and requires targeted proteomic validation (Biomedicines, 2024; https://doi.org/10.3390/biomedicines12112523) (vazquez2024extracellularvesiclesfrom pages 80-85, vazquez2024extracellularvesiclesfrom pages 85-89).

Key source list with URLs and dates
- SPOCK family review (domains, ECM roles, pathways; Oct 2024): Molecular Medicine Reports. https://doi.org/10.3892/mmr.2024.13355 (xiao2024spockmasterregulator pages 1-2, xiao2024spockmasterregulator pages 4-5, xiao2024spockmasterregulator pages 10-11, xiao2024spockmasterregulator pages 2-4, xiao2024spockmasterregulator pages 9-10).
- LUAD integrative and experimental study (EMT, immune evasion, drug repurposing; Dec 2023): Journal of Translational Medicine. https://doi.org/10.1186/s12967-023-04616-3 (liu2023spock1asa pages 16-18, liu2023spock1asa pages 1-2).
- LUAD EVs activate fibroblasts and upregulate SPOCK1 mRNA (Nov 2024): Biomedicines. https://doi.org/10.3390/biomedicines12112523 (vazquez2024extracellularvesiclesfrom pages 80-85, vazquez2024extracellularvesiclesfrom pages 65-70, vazquez2024extracellularvesiclesfrom pages 85-89).
- Stroke plasma proteomics (hyperacute ICH vs IS; AUC for SPOCK1 ≈ 0.78; Oct 2025): Biomarker Research. https://doi.org/10.1186/s40364-025-00848-1 (nunezjurado2025plasmaproteomicsuncovers pages 11-14, nunezjurado2025plasmaproteomicsuncovers pages 14-15).
- Osimertinib resistance mechanism via m6A and RBM15–SPOCK1 axis (Nov 2025): Oncogene. https://doi.org/10.1038/s41388-024-03220-z (li2025rbm15facilitatesosimertinib pages 7-9).

Conclusion
SPOCK1/Testican‑1 is a multi‑domain, secreted ECM proteoglycan that modulates protease activity and ECM remodeling and engages canonical oncogenic signaling programs (PI3K/AKT, Wnt/β‑catenin) to drive EMT, invasion, and immune evasion in cancer. Recent LUAD studies integrate bioinformatics and experimentation to implicate SPOCK1 as a prognostic/therapeutic biomarker and reveal a drug‑repurposing candidate that suppresses SPOCK1‑linked tumor growth. In the tumor microenvironment, LUAD EVs and TGFβ upregulate SPOCK1 transcripts in fibroblasts, suggesting roles in CAF activation that merit protein‑level validation. Beyond oncology, SPOCK1 shows promise as a plasma biomarker aiding rapid stroke subtype discrimination. These advances support continued mechanistic dissection and translational development of SPOCK1‑centric diagnostics and therapeutics (xiao2024spockmasterregulator pages 1-2, xiao2024spockmasterregulator pages 4-5, xiao2024spockmasterregulator pages 10-11, xiao2024spockmasterregulator pages 2-4, liu2023spock1asa pages 16-18, vazquez2024extracellularvesiclesfrom pages 80-85, vazquez2024extracellularvesiclesfrom pages 65-70, vazquez2024extracellularvesiclesfrom pages 85-89, nunezjurado2025plasmaproteomicsuncovers pages 11-14, nunezjurado2025plasmaproteomicsuncovers pages 14-15, li2025rbm15facilitatesosimertinib pages 7-9).

References

(xiao2024spockmasterregulator pages 1-2): Mingyuan Xiao, Jiancheng Xue, and Enli Jin. Spock: master regulator of malignant tumors (review). Molecular Medicine Reports, Oct 2024. URL: https://doi.org/10.3892/mmr.2024.13355, doi:10.3892/mmr.2024.13355. This article has 9 citations and is from a peer-reviewed journal.
(xiao2024spockmasterregulator pages 2-4): Mingyuan Xiao, Jiancheng Xue, and Enli Jin. Spock: master regulator of malignant tumors (review). Molecular Medicine Reports, Oct 2024. URL: https://doi.org/10.3892/mmr.2024.13355, doi:10.3892/mmr.2024.13355. This article has 9 citations and is from a peer-reviewed journal.
(xiao2024spockmasterregulator pages 4-5): Mingyuan Xiao, Jiancheng Xue, and Enli Jin. Spock: master regulator of malignant tumors (review). Molecular Medicine Reports, Oct 2024. URL: https://doi.org/10.3892/mmr.2024.13355, doi:10.3892/mmr.2024.13355. This article has 9 citations and is from a peer-reviewed journal.
(xiao2024spockmasterregulator pages 10-11): Mingyuan Xiao, Jiancheng Xue, and Enli Jin. Spock: master regulator of malignant tumors (review). Molecular Medicine Reports, Oct 2024. URL: https://doi.org/10.3892/mmr.2024.13355, doi:10.3892/mmr.2024.13355. This article has 9 citations and is from a peer-reviewed journal.
(liu2023spock1asa pages 16-18): Yafeng Liu, Tao Han, Jing Wu, Jiawei Zhou, Jianqiang Guo, Rui Miao, Zhi Xu, Yingru Xing, Ying Bai, and Dong Hu. Spock1, as a potential prognostic and therapeutic biomarker for lung adenocarcinoma, is associated with epithelial-mesenchymal transition and immune evasion. Journal of Translational Medicine, Dec 2023. URL: https://doi.org/10.1186/s12967-023-04616-3, doi:10.1186/s12967-023-04616-3. This article has 20 citations and is from a peer-reviewed journal.
(liu2023spock1asa pages 1-2): Yafeng Liu, Tao Han, Jing Wu, Jiawei Zhou, Jianqiang Guo, Rui Miao, Zhi Xu, Yingru Xing, Ying Bai, and Dong Hu. Spock1, as a potential prognostic and therapeutic biomarker for lung adenocarcinoma, is associated with epithelial-mesenchymal transition and immune evasion. Journal of Translational Medicine, Dec 2023. URL: https://doi.org/10.1186/s12967-023-04616-3, doi:10.1186/s12967-023-04616-3. This article has 20 citations and is from a peer-reviewed journal.
(vazquez2024extracellularvesiclesfrom pages 80-85): Jessica Angelina Trejo Vazquez, Rebecca Towle, Dylan Andrew Farnsworth, Masih Sarafan, William Wallace Lockwood, and Cathie Garnis. Extracellular vesicles from lung adenocarcinoma cells induce activation of different cancer-associated fibroblast subtypes. Biomedicines, 12:2523, Nov 2024. URL: https://doi.org/10.3390/biomedicines12112523, doi:10.3390/biomedicines12112523. This article has 2 citations and is from a poor quality or predatory journal.
(vazquez2024extracellularvesiclesfrom pages 65-70): Jessica Angelina Trejo Vazquez, Rebecca Towle, Dylan Andrew Farnsworth, Masih Sarafan, William Wallace Lockwood, and Cathie Garnis. Extracellular vesicles from lung adenocarcinoma cells induce activation of different cancer-associated fibroblast subtypes. Biomedicines, 12:2523, Nov 2024. URL: https://doi.org/10.3390/biomedicines12112523, doi:10.3390/biomedicines12112523. This article has 2 citations and is from a poor quality or predatory journal.
(vazquez2024extracellularvesiclesfrom pages 85-89): Jessica Angelina Trejo Vazquez, Rebecca Towle, Dylan Andrew Farnsworth, Masih Sarafan, William Wallace Lockwood, and Cathie Garnis. Extracellular vesicles from lung adenocarcinoma cells induce activation of different cancer-associated fibroblast subtypes. Biomedicines, 12:2523, Nov 2024. URL: https://doi.org/10.3390/biomedicines12112523, doi:10.3390/biomedicines12112523. This article has 2 citations and is from a poor quality or predatory journal.
(nunezjurado2025plasmaproteomicsuncovers pages 11-14): David Núñez-Jurado, Alejandro Fernández-Vega, Carmen del Río, Anna Penalba, Laia Llucià-Carol, Elena Muiño-Acuña, Garbiñe Ezcurra-Díaz, Marina Guasch-Jiménez, Natalia Cullell, Gemma Serrano-Heras, Lourdes Arias-Salazar, Cristòfol Vives-Bauza, Silvia Tur, Xabier Urra, Mar Castellanos, Jerzy Krupinski, Marimar Freijo-Guerrero, Jordi Jiménez-Conde, Isabel Fernández-Pérez, Tomás Segura, Joan Marti-Fabregas, Israel Férnandez-Cadenas, and Joan Montaner. Plasma proteomics uncovers divergent molecular signatures in ischemic stroke and intracerebral hemorrhage. Biomarker Research, Oct 2025. URL: https://doi.org/10.1186/s40364-025-00848-1, doi:10.1186/s40364-025-00848-1. This article has 0 citations and is from a peer-reviewed journal.
(nunezjurado2025plasmaproteomicsuncovers pages 14-15): David Núñez-Jurado, Alejandro Fernández-Vega, Carmen del Río, Anna Penalba, Laia Llucià-Carol, Elena Muiño-Acuña, Garbiñe Ezcurra-Díaz, Marina Guasch-Jiménez, Natalia Cullell, Gemma Serrano-Heras, Lourdes Arias-Salazar, Cristòfol Vives-Bauza, Silvia Tur, Xabier Urra, Mar Castellanos, Jerzy Krupinski, Marimar Freijo-Guerrero, Jordi Jiménez-Conde, Isabel Fernández-Pérez, Tomás Segura, Joan Marti-Fabregas, Israel Férnandez-Cadenas, and Joan Montaner. Plasma proteomics uncovers divergent molecular signatures in ischemic stroke and intracerebral hemorrhage. Biomarker Research, Oct 2025. URL: https://doi.org/10.1186/s40364-025-00848-1, doi:10.1186/s40364-025-00848-1. This article has 0 citations and is from a peer-reviewed journal.
(xiao2024spockmasterregulator pages 9-10): Mingyuan Xiao, Jiancheng Xue, and Enli Jin. Spock: master regulator of malignant tumors (review). Molecular Medicine Reports, Oct 2024. URL: https://doi.org/10.3892/mmr.2024.13355, doi:10.3892/mmr.2024.13355. This article has 9 citations and is from a peer-reviewed journal.
(li2025rbm15facilitatesosimertinib pages 7-9): Hongxiang Li, Yin Li, Xiao-xiao Zheng, Fangqian Chen, Shufeng Zhang, Shu-ping Xu, Yinyu Mu, W. Shen, Jingtao Tong, Hang Chen, Zeyang Hu, Jiaheng Zhang, Keyue Qiu, Wei Chen, Xinghua Cheng, and Guodong Xu. Rbm15 facilitates osimertinib resistance of lung adenocarcinoma through m6a-dependent epigenetic silencing of spock1. Oncogene, 44:307-321, Nov 2025. URL: https://doi.org/10.1038/s41388-024-03220-z, doi:10.1038/s41388-024-03220-z. This article has 17 citations and is from a domain leading peer-reviewed journal.

Citations

xiao2024spockmasterregulator pages 1-2
xiao2024spockmasterregulator pages 2-4
xiao2024spockmasterregulator pages 4-5
xiao2024spockmasterregulator pages 10-11
vazquez2024extracellularvesiclesfrom pages 80-85
vazquez2024extracellularvesiclesfrom pages 65-70
vazquez2024extracellularvesiclesfrom pages 85-89
nunezjurado2025plasmaproteomicsuncovers pages 11-14
nunezjurado2025plasmaproteomicsuncovers pages 14-15
xiao2024spockmasterregulator pages 9-10
https://doi.org/10.3892/mmr.2024.13355
https://doi.org/10.3892/mmr.2024.13355;
https://doi.org/10.1186/s12967-023-04616-3
https://doi.org/10.3390/biomedicines12112523
https://doi.org/10.1186/s40364-025-00848-1
https://doi.org/10.1038/s41388-024-03220-z
https://doi.org/10.3390/biomedicines12112523;
https://doi.org/10.1186/s12967-023-04616-3;
https://doi.org/10.3892/mmr.2024.13355,
https://doi.org/10.1186/s12967-023-04616-3,
https://doi.org/10.3390/biomedicines12112523,
https://doi.org/10.1186/s40364-025-00848-1,
https://doi.org/10.1038/s41388-024-03220-z,

📄 View Raw YAML

id: Q08629
gene_symbol: SPOCK1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'SPOCK1 encodes testican-1, a secreted multidomain proteoglycan of the
  extracellular matrix. The 439 amino acid protein is modified with chondroitin sulfate
  and heparan sulfate glycosaminoglycan chains attached to serine residues in the
  C-terminal region. Testican-1 has a modular architecture containing a follistatin-like
  domain, an acidic region, extracellular calcium-binding domains, Kazal-like protease
  inhibitor domains, and a thyroglobulin type-1 domain. The protein functions as a
  structural ECM component that modulates cell-substrate adhesion and inhibits multiple
  classes of proteases including metalloendopeptidases (via direct binding to MT1-MMP
  and MT3-MMP), cysteine proteases (cathepsin L with Ki=0.7 nM), and serine proteases.
  Testican-1 is highly expressed in brain (particularly cerebellum, with immunolocalization
  to postsynaptic densities), and also found in testis and endothelial cells. The
  protein plays important roles in ECM organization, regulation of neuron attachment
  and neurite outgrowth, and protease regulation in both intracellular and extracellular
  contexts.'
existing_annotations:
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Testican-1 is a secreted proteoglycan that localizes to and is a structural
      component of the extracellular matrix. Multiple lines of evidence support this
      core localization.
    action: ACCEPT
    reason: IBA annotation is well-supported by experimental evidence. UniProt states
      "Secreted, extracellular space, extracellular matrix". Multiple proteomics studies
      (PMID:27068509, PMID:32055794, PMID:33266304) identified testican-1 in ECM preparations
      using HDA evidence. The protein is described as an ECM proteoglycan in the original
      characterization (PMID:8389704). This is a core function of testican-1.
    supported_by:
    - reference_id: PMID:8389704
      supporting_text: 'The molecular characterization of a human testicular proteoglycan,
        the progenitor of a seminal plasma glycosaminoglycan-bearing peptide, was
        achieved by cDNA cloning.'
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
        matrix.'
    - reference_id: file:human/SPOCK1/SPOCK1-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0008191
    label: metalloendopeptidase inhibitor activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Testican-1 directly inhibits membrane-type matrix metalloproteinases
      (MT-MMPs) including MT1-MMP and MT3-MMP, preventing pro-MMP-2 activation. This
      is a core molecular function.
    action: ACCEPT
    reason: IBA annotation is supported by experimental evidence from PMID:11751414
      showing direct interaction with MT1-MMP and MT3-MMP and inhibition of pro-MMP-2
      activation. While this study focused on testican-3, it explicitly states "Expression
      of testican 1 or testican 3 but not testican 2 also inhibited pro-MMP-2 activation".
      This metalloproteinase inhibitor activity is a core function of testican-1.
    supported_by:
    - reference_id: PMID:11751414
      supporting_text: 'Expression of testican 1 or testican 3 but not testican 2
        also inhibited pro-MMP-2 activation by either MT1-MMP or MT3-MMP.'
- term:
    id: GO:0010810
    label: regulation of cell-substrate adhesion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Testican-1 regulates cell-substrate adhesion, with experimental evidence
      showing it inhibits Neuro-2a cell attachment. The IBA term appropriately captures
      this regulatory function.
    action: ACCEPT
    reason: IBA annotation is supported by experimental evidence from PMID:12853036
      and PMID:8389704. The protein is explicitly described as resembling "modulators
      of cell social behaviour" and experimental data shows it inhibits neuron attachment
      (PMID:12853036). This is a core function related to ECM-mediated cell adhesion
      modulation.
    supported_by:
    - reference_id: PMID:8389704
      supporting_text: 'Testican, a multidomain testicular proteoglycan resembling
        modulators of cell social behaviour.'
    - reference_id: PMID:12853036
      supporting_text: 'We demonstrate that testican inhibits attachment of Neuro-2a
        cells and their ability to form neurite extensions.'
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Testican-1 is secreted to the extracellular space as confirmed by UniProt
      and experimental detection in extracellular fluids.
    action: ACCEPT
    reason: IBA annotation is consistent with the protein being secreted (signal peptide
      residues 1-21) and detected in extracellular locations including seminal plasma
      and as part of the ECM. This is a core localization.
    supported_by:
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
        matrix.'
    - reference_id: PMID:14511383
      supporting_text: 'Testican-1, a secreted proteoglycan enriched in brain'
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Testican-1 contains extracellular calcium-binding (EC) domains similar
      to those in BM-40/SPARC. Direct experimental evidence confirms calcium binding
      activity.
    action: ACCEPT
    reason: IBA annotation is supported by both sequence analysis (InterPro IPR019577
      SPARC/Testican Ca-binding domain) and experimental evidence from PMID:9323035
      demonstrating calcium binding with Kd=68 microM. The EC domain shows structural
      changes upon calcium depletion. This is a core molecular function.
    supported_by:
    - reference_id: PMID:9323035
      supporting_text: 'The extracellular calcium-binding (EC) module of human testican
        (115 residues) was obtained in native form by recombinant production in mammalian
        cell culture and thus shown to represent an independently folding domain.
        This module showed a large loss in alpha-helix upon calcium depletion. Apparently
        only one of the two EF hands binds calcium, with a moderate affinity (Kd =68
        microM)'
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate IEA annotation based on InterPro domain IPR019577. Redundant
      with IBA and IDA evidence for same term.
    action: ACCEPT
    reason: This IEA annotation is based on the presence of the SPARC/Testican calcium-binding
      domain (InterPro IPR019577) and is consistent with experimental evidence. While
      duplicate, it provides computational confirmation of the calcium-binding function.
    supported_by:
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'InterPro: IPR019577; SPARC/Testican_Ca-bd-dom'
- term:
    id: GO:0008191
    label: metalloendopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Duplicate IEA annotation from ARBA machine learning. Redundant with IBA
      and IDA evidence for same term.
    action: ACCEPT
    reason: This IEA annotation provides computational support for the metalloendopeptidase
      inhibitor activity that is experimentally validated by IBA and IDA evidence.
      Acceptable as supporting evidence.
    supported_by:
    - reference_id: GO_REF:0000117
      supporting_text: Electronic annotation by ARBA machine learning models
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  review:
    summary: Generic protein binding annotation from binary interactome study. Too
      vague to be informative about testican-1 function.
    action: REMOVE
    reason: The term "protein binding" provides no functional information about testican-1's
      specific role. While the protein does bind to other proteins (MT-MMPs, cathepsin
      L, etc.), these interactions are better captured by more specific terms like
      metalloendopeptidase inhibitor activity and cysteine-type endopeptidase inhibitor
      activity. PMID:32296183 is a high-throughput interactome study that does not
      provide specific functional context.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: 'A reference map of the human binary protein interactome'
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: HDA
  original_reference_id: PMID:27068509
  review:
    summary: Testican-1 functions as a structural component of the ECM, identified
      in matrisome proteomics studies. This is a core molecular function.
    action: ACCEPT
    reason: HDA annotation from ECM proteomics study is appropriate. As a proteoglycan
      with GAG chains that localizes to the ECM, testican-1 contributes to ECM structure.
      The modular domain architecture and proteoglycan nature support this structural
      role.
    supported_by:
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'O-glycosylated. Glycosaminoglycan that contains chondroitin
        sulfate and heparan sulfate.'
    - reference_id: PMID:8389704
      supporting_text: 'Testican is the progenitor of the unique heparan/chondroitin-sulfate-bearing
        peptide present in human seminal plasma'
    - reference_id: PMID:27068509
      supporting_text: 'Apr 11. Extracellular matrix remodelling in response to venous
        hypertension: proteomics of human varicose veins.'
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:27068509
  review:
    summary: Duplicate HDA annotation for ECM localization from varicose vein ECM
      proteomics. Redundant with IBA annotation.
    action: ACCEPT
    reason: This HDA annotation provides independent proteomics evidence for ECM localization
      from a study on extracellular matrix remodeling in human varicose veins. Multiple
      independent HDA studies confirm this core localization.
    supported_by:
    - reference_id: PMID:27068509
      supporting_text: 'Apr 11. Extracellular matrix remodelling in response to venous
        hypertension: proteomics of human varicose veins.'
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:32055794
  review:
    summary: Duplicate HDA annotation for ECM localization from 3D ECM mapping study.
      Redundant with IBA and other HDA annotations.
    action: ACCEPT
    reason: Additional proteomics evidence for ECM localization from independent study
      on 3D mapping of native extracellular matrix. Reinforces core localization.
    supported_by:
    - reference_id: PMID:32055794
      supporting_text: 3D mapping of native extracellular matrix reveals cellular
        responses to the microenvironment.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:33266304
  review:
    summary: Duplicate HDA annotation for ECM localization from matrisome characterization
      study. Redundant with IBA and other HDA annotations.
    action: ACCEPT
    reason: Additional proteomics evidence for ECM localization from Divide-and-Conquer
      Matrisome Protein (DC-MaP) strategy study. Multiple independent HDA studies
      provide strong support for this core localization.
    supported_by:
    - reference_id: PMID:33266304
      supporting_text: 'Divide-and-Conquer Matrisome Protein (DC-MaP) Strategy: An
        MS-Friendly Approach to Proteomic Matrisome Characterization.'
- term:
    id: GO:0001558
    label: regulation of cell growth
  evidence_type: NAS
  original_reference_id: PMID:8389704
  review:
    summary: Original paper describes testican-1 as resembling modulators of cell
      social behavior, but provides no direct experimental evidence for regulation
      of cell growth.
    action: KEEP_AS_NON_CORE
    reason: The annotation is based on NAS (non-traceable author statement) from the
      original characterization paper. While the multidomain structure suggests potential
      roles in cell proliferation, this is not a core function based on current evidence.
      The primary characterized functions are ECM structural roles and protease inhibition.
    supported_by:
    - reference_id: PMID:8389704
      supporting_text: 'Its protein core encompasses several domains encountered in
        various proteins associated with adhesion, migration and cell proliferation.'
- term:
    id: GO:0001764
    label: neuron migration
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on orthology to mouse testican-1 (Q62288). While
      testican-1 affects neuron attachment, direct evidence for neuron migration is
      limited.
    action: KEEP_AS_NON_CORE
    reason: ISS annotation transferred from mouse ortholog. While testican-1 clearly
      affects neuronal cell adhesion and neurite extension (PMID:12853036), migration
      is a distinct process. This is potentially valid but peripheral to the core
      ECM structural and protease inhibitor functions.
    supported_by:
    - reference_id: GO_REF:0000024
      supporting_text: Manual transfer from mouse ortholog UniProtKB:Q62288
- term:
    id: GO:0004867
    label: serine-type endopeptidase inhibitor activity
  evidence_type: NAS
  original_reference_id: PMID:14511383
  review:
    summary: NAS annotation suggesting serine protease inhibitor activity based on
      Kazal-like domain presence, but experimental evidence in same paper focused
      on cysteine protease inhibition.
    action: UNDECIDED
    reason: Kazal-like domains are typically serine protease inhibitors, and testican-1
      contains a Kazal-like domain (residues 130-182). However, PMID:14511383 experimentally
      demonstrated cysteine protease (cathepsin L) inhibition but did not test serine
      proteases. The NAS evidence is weak without direct experimental validation.
      Would need experimental testing to confirm.
    supported_by:
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'DOMAIN 130..182 Kazal-like'
    - reference_id: PMID:14511383
      supporting_text: Human proteoglycan testican-1 inhibits the lysosomal cysteine
        protease cathepsin L.
- term:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:14511383
  review:
    summary: Direct experimental demonstration that testican-1 inhibits cathepsin
      L with Ki=0.7 nM via its thyroglobulin type-1 domain. This is a core molecular
      function.
    action: ACCEPT
    reason: Strong IDA evidence from PMID:14511383 showing potent and specific inhibition
      of cathepsin L (Ki=0.7 nM) but not cathepsin B. The thyroglobulin domain mediates
      this activity. This is a well-characterized core function of testican-1.
    supported_by:
    - reference_id: PMID:14511383
      supporting_text: 'We demonstrate that purified recombinant human testican-1
        is a strong competitive inhibitor of the lysosomal cysteine protease, cathepsin
        L, with a Ki of 0.7 nM, but it does not inhibit the structurally related lysosomal
        cysteine protease cathepsin B.'
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:9323035
  review:
    summary: Duplicate IDA annotation for calcium binding. Redundant with IBA annotation
      for same term, both supported by same experimental evidence.
    action: ACCEPT
    reason: This IDA annotation provides direct experimental evidence for calcium
      binding (Kd=68 microM) and is the primary experimental reference. Consistent
      with IBA and IEA annotations for the same function.
    supported_by:
    - reference_id: PMID:9323035
      supporting_text: 'Apparently only one of the two EF hands binds calcium, with
        a moderate affinity (Kd =68 microM)'
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IDA
  original_reference_id: PMID:14511383
  review:
    summary: Duplicate IDA annotation for extracellular space localization. Redundant
      with IBA annotation.
    action: ACCEPT
    reason: IDA evidence from purification and characterization of secreted testican-1
      from cell culture medium. Supports IBA annotation for same localization.
    supported_by:
    - reference_id: PMID:14511383
      supporting_text: 'Testican-1, a secreted proteoglycan enriched in brain'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation based on mouse ortholog suggesting cytoplasmic localization.
      Inconsistent with primary secreted localization.
    action: REMOVE
    reason: Testican-1 has a signal peptide (residues 1-21) and is characterized as
      a secreted proteoglycan. UniProt annotation states "Secreted, extracellular
      space, extracellular matrix" with no mention of cytoplasmic localization. While
      the protein may transiently pass through the cytoplasm during secretion, cytoplasm
      is not a functional localization for this protein. This ISS annotation from
      mouse ortholog appears incorrect.
    supported_by:
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'SIGNAL 1..21; SUBCELLULAR LOCATION: Secreted, extracellular
        space, extracellular matrix.'
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: NAS
  original_reference_id: PMID:8389704
  review:
    summary: NAS annotation for cell adhesion based on structural similarity to cell
      adhesion modulators. Supported by experimental data on adhesion regulation.
    action: ACCEPT
    reason: While NAS evidence is weak, the annotation is supported by the protein's
      domain structure and experimental evidence from PMID:12853036 showing regulation
      of cell attachment. This is appropriately a general cell adhesion term that
      encompasses the more specific regulation of cell-substrate adhesion function.
    supported_by:
    - reference_id: PMID:8389704
      supporting_text: 'Testican, a multidomain testicular proteoglycan resembling
        modulators of cell social behaviour.'
    - reference_id: PMID:12853036
      supporting_text: 'We demonstrate that testican inhibits attachment of Neuro-2a
        cells'
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: NAS
  original_reference_id: PMID:9181134
  review:
    summary: NAS annotation for nervous system development based on brain expression
      and postsynaptic localization. Testican-1 is enriched in brain.
    action: KEEP_AS_NON_CORE
    reason: While testican-1 is highly expressed in brain and affects neuron attachment/neurite
      extension, nervous system development is a broad process term that may be peripheral
      to the core molecular functions (ECM structure, protease inhibition, adhesion
      modulation). The NAS evidence is weak but consistent with expression patterns.
    supported_by:
    - reference_id: PMID:9181134
      supporting_text: 'Structural analysis, a main expression in nervous system and
        preliminary assignment of the human gene in a critical region for neuropathologies,
        suggest that SPOCK may be of importance in neural development'
- term:
    id: GO:0008191
    label: metalloendopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:11751414
  review:
    summary: Duplicate IDA annotation for metalloendopeptidase inhibitor activity.
      Redundant with IBA annotation.
    action: ACCEPT
    reason: IDA annotation provides direct experimental evidence for MT-MMP inhibition.
      This is the primary experimental reference supporting the IBA annotation. Core
      molecular function.
    supported_by:
    - reference_id: PMID:11751414
      supporting_text: 'Expression of testican 1 or testican 3 but not testican 2
        also inhibited pro-MMP-2 activation by either MT1-MMP or MT3-MMP.'
- term:
    id: GO:0010812
    label: negative regulation of cell-substrate adhesion
  evidence_type: IDA
  original_reference_id: PMID:12853036
  review:
    summary: Direct experimental evidence showing testican-1 inhibits Neuro-2a cell
      attachment to substrate. More specific than the IBA term for regulation of cell-substrate
      adhesion.
    action: ACCEPT
    reason: Strong IDA evidence showing testican-1 inhibits cell attachment when coated
      on substrate, blocking attachment sites. This negative regulatory function is
      well-characterized and represents a core activity related to ECM-mediated adhesion
      modulation.
    supported_by:
    - reference_id: PMID:12853036
      supporting_text: 'We demonstrate that testican inhibits attachment of Neuro-2a
        cells and their ability to form neurite extensions. Both testican proteoglycan
        and the core glycoprotein that has been depleted of chondroitin sulfate inhibit
        cell attachment. Pre-treatment of the culture substratum with testican inhibits
        Neuro-2a attachment'
- term:
    id: GO:0010977
    label: negative regulation of neuron projection development
  evidence_type: IDA
  original_reference_id: PMID:12853036
  review:
    summary: Direct experimental evidence showing testican-1 inhibits neurite extension
      in Neuro-2a cells. Represents a specific neuronal function.
    action: ACCEPT
    reason: Strong IDA evidence from PMID:12853036 demonstrating inhibition of neurite
      extensions. This is a well-characterized activity but may be considered non-core
      as it represents a tissue-specific manifestation of the broader adhesion modulation
      function.
    supported_by:
    - reference_id: PMID:12853036
      supporting_text: 'We demonstrate that testican inhibits attachment of Neuro-2a
        cells and their ability to form neurite extensions.'
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: NAS
  original_reference_id: PMID:9181134
  review:
    summary: NAS annotation for postsynaptic density localization based on immunoelectron
      microscopy showing selective localization in postsynaptic densities.
    action: KEEP_AS_NON_CORE
    reason: The annotation is based on immunoelectron microscopy data from PMID:9181134
      showing localization to postsynaptic densities of pyramidal neurons and Purkinje
      cells. However, this is a specialized sub-localization within the broader CNS
      expression pattern and represents a non-core, tissue-specific localization.
    supported_by:
    - reference_id: PMID:9181134
      supporting_text: 'Immunoelectron microscopy showed the antigen selectively localized
        in the post-synaptic density of scattered pyramidal neurons and Purkinje cells.'
- term:
    id: GO:0016528
    label: sarcoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for sarcoplasm localization based on mouse ortholog. Inconsistent
      with secreted nature of protein.
    action: REMOVE
    reason: Similar to the cytoplasm annotation, sarcoplasm is inconsistent with testican-1
      being a secreted ECM proteoglycan. This ISS annotation from mouse ortholog appears
      incorrect for a protein with a signal peptide that functions in the extracellular
      space.
    supported_by:
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
        matrix.'
- term:
    id: GO:0021953
    label: central nervous system neuron differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for CNS neuron differentiation based on mouse ortholog.
      Represents a developmental process.
    action: KEEP_AS_NON_CORE
    reason: ISS annotation from mouse ortholog. While testican-1 is highly expressed
      in brain and affects neuronal cell behavior, neuron differentiation is a broad
      developmental process that is peripheral to the core ECM structural and protease
      inhibitor functions.
    supported_by:
    - reference_id: GO_REF:0000024
      supporting_text: Manual transfer from mouse ortholog
- term:
    id: GO:0022008
    label: neurogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for neurogenesis based on mouse ortholog. Very broad developmental
      process term.
    action: KEEP_AS_NON_CORE
    reason: ISS annotation from mouse ortholog. Neurogenesis is an extremely broad
      process term. While testican-1 affects neuron behavior and is expressed in brain,
      this broad developmental process is peripheral to core functions.
    supported_by:
    - reference_id: GO_REF:0000024
      supporting_text: Manual transfer from mouse ortholog
- term:
    id: GO:0031594
    label: neuromuscular junction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for neuromuscular junction localization based on mouse
      ortholog. Specialized tissue-specific localization.
    action: KEEP_AS_NON_CORE
    reason: ISS annotation from mouse ortholog suggesting localization to neuromuscular
      junctions. This is a specialized tissue-specific localization that is peripheral
      to the core ECM localization. May be valid but represents a minor sub-localization.
    supported_by:
    - reference_id: GO_REF:0000024
      supporting_text: Manual transfer from mouse ortholog
- term:
    id: GO:0033268
    label: node of Ranvier
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: ISS annotation for node of Ranvier localization based on mouse ortholog.
      Highly specialized neuronal structure.
    action: KEEP_AS_NON_CORE
    reason: ISS annotation from mouse ortholog suggesting localization to nodes of
      Ranvier. This is a highly specialized sub-localization within myelinated axons
      that is peripheral to the core ECM function. May be valid but represents a minor
      tissue-specific localization.
    supported_by:
    - reference_id: GO_REF:0000024
      supporting_text: Manual transfer from mouse ortholog
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for collagen binding found in UniProt but not in GOA file.
      Testican-1 is an ECM proteoglycan that may interact with collagen.
    action: NEW
    reason: This IBA annotation appears in UniProt (DR GO; GO:0005518; F:collagen
      binding; IBA:GO_Central) but was not included in the GOA file provided. As an
      ECM proteoglycan, testican-1 may interact with collagen fibrils, though direct
      experimental evidence is lacking. PMID:9323035 tested the EC module for collagen
      binding and found "No clear evidence was obtained for collagen binding", suggesting
      this IBA annotation may be over-prediction. Requires experimental validation.
    supported_by:
    - reference_id: PMID:9323035
      supporting_text: 'No clear evidence was obtained for collagen binding, indicating
        that EC modules found in different proteins may not share similar functions.'
- term:
    id: GO:0050840
    label: extracellular matrix binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: IBA annotation for ECM binding found in UniProt but not in GOA file.
      As an ECM proteoglycan, testican-1 likely interacts with ECM components.
    action: NEW
    reason: This IBA annotation appears in UniProt (DR GO; GO:0050840; F:extracellular
      matrix binding; IBA:GO_Central) but was not in the GOA file. As a proteoglycan
      with GAG chains that localizes to the ECM and modulates cell-matrix interactions,
      ECM binding is a reasonable function. However, specific binding partners beyond
      MT-MMPs have not been well characterized. This represents a core function consistent
      with the protein's role in ECM organization.
    supported_by:
    - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
      supporting_text: 'May play a role in cell-cell and cell-matrix interactions.'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms.
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity.
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:11751414
  title: Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2
    activation and tumor invasion by testican 3 and its splicing variant gene product,
    N-Tes.
  findings: []
- id: PMID:12853036
  title: Testican-1 inhibits attachment of Neuro-2a cells.
  findings: []
- id: PMID:14511383
  title: Human proteoglycan testican-1 inhibits the lysosomal cysteine protease cathepsin
    L.
  findings: []
- id: PMID:27068509
  title: 'Extracellular matrix remodelling in response to venous hypertension: proteomics
    of human varicose veins.'
  findings: []
- id: PMID:32055794
  title: 3D mapping of native extracellular matrix reveals cellular responses to the
    microenvironment.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:33266304
  title: 'Divide-and-Conquer Matrisome Protein (DC-MaP) Strategy: An MS-Friendly Approach
    to Proteomic Matrisome Characterization.'
  findings: []
- id: PMID:8389704
  title: Testican, a multidomain testicular proteoglycan resembling modulators of
    cell social behaviour.
  findings: []
- id: PMID:9181134
  title: '[Cloning of testican/SPOCK in man and mouse. Neuromuscular expression perspectives
    in pathology].'
  findings: []
- id: PMID:9323035
  title: Properties of the extracellular calcium binding module of the proteoglycan
    testican.
  findings: []
- id: file:human/SPOCK1/SPOCK1-deep-research-falcon.md
  title: Deep research report on SPOCK1
  findings: []
core_functions:
- description: Testican-1 functions as a structural component of the extracellular
    matrix, contributing to ECM organization through its proteoglycan nature with
    chondroitin sulfate and heparan sulfate GAG chains. Identified in multiple ECM
    proteomics studies.
  molecular_function:
    id: GO:0005201
    label: extracellular matrix structural constituent
  locations:
  - id: GO:0031012
    label: extracellular matrix
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:8389704
    supporting_text: 'Testican is the progenitor of the unique heparan/chondroitin-sulfate-bearing
      peptide present in human seminal plasma'
  - reference_id: PMID:27068509
    supporting_text: 'METHODS AND RESULTS: To understand the consequences of venous
      hypertension, normal and varicose veins were evaluated using proteomics approaches
      targeting the extracellular matrix'
  - reference_id: file:human/SPOCK1/SPOCK1-uniprot.txt
    supporting_text: 'O-glycosylated. Glycosaminoglycan that contains chondroitin
      sulfate and heparan sulfate.'
- description: Testican-1 directly inhibits membrane-type matrix metalloproteinases
    (MT1-MMP and MT3-MMP), preventing pro-MMP-2 activation through direct protein-protein
    interaction.
  molecular_function:
    id: GO:0008191
    label: metalloendopeptidase inhibitor activity
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:11751414
    supporting_text: 'Expression of testican 1 or testican 3 but not testican 2 also
      inhibited pro-MMP-2 activation by either MT1-MMP or MT3-MMP.'
- description: Testican-1 is a potent competitive inhibitor of cathepsin L (Ki=0.7
    nM) via its thyroglobulin type-1 domain. Does not inhibit cathepsin B. Active
    at both pH 5.5 and pH 7.2, functioning in both intracellular vesicles and extracellular
    space.
  molecular_function:
    id: GO:0004869
    label: cysteine-type endopeptidase inhibitor activity
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:14511383
    supporting_text: 'We demonstrate that purified recombinant human testican-1 is
      a strong competitive inhibitor of the lysosomal cysteine protease, cathepsin
      L, with a Ki of 0.7 nM, but it does not inhibit the structurally related lysosomal
      cysteine protease cathepsin B.'
- description: The extracellular calcium-binding (EC) module contains EF-hand motifs
    and binds calcium with moderate affinity (Kd=68 microM). The module undergoes
    conformational change upon calcium binding.
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  supported_by:
  - reference_id: PMID:9323035
    supporting_text: 'Apparently only one of the two EF hands binds calcium, with
      a moderate affinity (Kd =68 microM)'
- description: Testican-1 binds to extracellular matrix components and modulates cell-matrix
    interactions, inhibiting neuron attachment to substrate and blocking neurite extension.
    This function is mediated by both the proteoglycan form and the core protein depleted
    of chondroitin sulfate.
  molecular_function:
    id: GO:0050840
    label: extracellular matrix binding
  directly_involved_in:
  - id: GO:0010812
    label: negative regulation of cell-substrate adhesion
  - id: GO:0010977
    label: negative regulation of neuron projection development
  - id: GO:0010810
    label: regulation of cell-substrate adhesion
  locations:
  - id: GO:0005576
    label: extracellular region
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: PMID:12853036
    supporting_text: 'We demonstrate that testican inhibits attachment of Neuro-2a
      cells and their ability to form neurite extensions. Both testican proteoglycan
      and the core glycoprotein that has been depleted of chondroitin sulfate inhibit
      cell attachment. Pre-treatment of the culture substratum with testican inhibits
      Neuro-2a attachment, but pre-treatment of the cells with testican does not inhibit
      their attachment. Testican, therefore, blocks attachment sites on cultureware
      and may also block attachment sites in the extracellular matrix of the brain.'

SPOCK1

Gene Description

Existing Annotations Review

Core Functions

Testican-1 functions as a structural component of the extracellular matrix, contributing to ECM organization through its proteoglycan nature with chondroitin sulfate and heparan sulfate GAG chains. Identified in multiple ECM proteomics studies.

Testican-1 directly inhibits membrane-type matrix metalloproteinases (MT1-MMP and MT3-MMP), preventing pro-MMP-2 activation through direct protein-protein interaction.

Testican-1 is a potent competitive inhibitor of cathepsin L (Ki=0.7 nM) via its thyroglobulin type-1 domain. Does not inhibit cathepsin B. Active at both pH 5.5 and pH 7.2, functioning in both intracellular vesicles and extracellular space.

The extracellular calcium-binding (EC) module contains EF-hand motifs and binds calcium with moderate affinity (Kd=68 microM). The module undergoes conformational change upon calcium binding.

Testican-1 binds to extracellular matrix components and modulates cell-matrix interactions, inhibiting neuron attachment to substrate and blocking neurite extension. This function is mediated by both the proteoglycan form and the core protein depleted of chondroitin sulfate.

References

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