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 [high-throughput study]
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 space

Supporting Evidence:

PMID:8389704
Testican is the progenitor of the unique heparan/chondroitin-sulfate-bearing peptide present in human seminal plasma
PMID:27068509
ECM proteomics study identifying testican-1 in varicose vein 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 space

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 space

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 space 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.
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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
            [high-throughput study]'
  - 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:0005615
        label: extracellular space
    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: ECM proteomics study identifying testican-1 in varicose
          vein 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:0005615
        label: extracellular space
    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:0005615
        label: extracellular space
    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:0005615
        label: extracellular space
      - 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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If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

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