GO:2000098 negative regulation of smooth muscle cell-matrix adhesion: Signaling Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2000098 describes any process that stops, prevents, or reduces the frequency, rate or extent of smooth muscle cell-matrix adhesion.
• Smooth muscle cell-matrix adhesion is dynamically controlled by kinases, phosphatases, integrins and focal adhesion proteins such as FAK, ILK, kindlin-2 and Poldip2.
• cGMP-dependent protein kinase (PKG) signaling suppresses pulmonary vascular smooth muscle cell adhesion and migration, especially under hypoxia.
• RhoA and Src selectively tune cytoskeletal tension and cell-matrix adhesion, providing druggable nodes for negative regulation.
• Loss of negative regulation contributes to intimal thickening, vascular remodeling and proliferative vascular disease.
• CRISPR knockout, point-mutation, knock-in and overexpression models allow causal testing of candidate negative regulators in smooth muscle cells.
Description
Smooth muscle cells (SMCs) are contractile cells that anchor to the extracellular matrix (ECM) through integrin-based adhesions, and the strength and turnover of these adhesions determine whether SMCs remain quiescent or become migratory and proliferative. GO:2000098, negative regulation of smooth muscle cell-matrix adhesion, captures the biological processes that stop, prevent, or reduce the frequency, rate or extent of this adhesion. Because excessive or persistent SMC-ECM adhesion drives vascular remodeling, intimal thickening and proliferative vascular disease, the negative regulators defined by this term are attractive therapeutic and research targets.
negative regulation of smooth muscle cell-matrix adhesion At A Glance
| GO ID | GO:2000098 |
|---|---|
| GO term | negative regulation of smooth muscle cell-matrix adhesion |
| Ontology | biological_process |
| Synonym | none |
| Major function | Stops, prevents or reduces the frequency, rate or extent of smooth muscle cell-matrix adhesion |
| Upstream regulators | PKG, RhoA, Src, ILK, kindlin-2, FAK, Poldip2 |
| Cellular context | Focal adhesions, integrin complexes and cytoskeletal tension in smooth muscle cells |
| Disease relevance | Intimal thickening, vascular remodeling and proliferative vascular disease |
| Research methods | CRISPR KO/point mutation/knock-in/overexpression, adhesion assays, imaging, proteomics |
What Is GO:2000098?
GO:2000098 is a biological_process term meaning any process that stops, prevents, or reduces the frequency, rate or extent of smooth muscle cell-matrix adhesion. In practice, it includes signaling events, cytoskeletal rearrangements and protein-stability changes that weaken or disassemble integrin-mediated contacts between smooth muscle cells and the surrounding matrix.
Why Is negative regulation of smooth muscle cell-matrix adhesion Important in Cell Biology?
Negative regulation of smooth muscle cell-matrix adhesion is important because it acts as a brake on SMC migration and proliferation, and loss of this brake is linked to pathological vascular remodeling such as intimal thickening. Understanding the kinases, adaptors and matrix-synthesis regulators that execute this brake provides mechanistic insight into vascular disease and identifies candidate targets for intervention.
• Controls whether smooth muscle cells remain quiescent or become migratory and proliferative.
• Integrates cGMP/PKG signaling with adhesion turnover in pulmonary vascular smooth muscle.
• Links RhoA and Src cytoskeletal tension pathways to cell-matrix adhesion strength.
• Involves integrin-linked kinase (ILK) and beta-catenin signaling in vascular smooth muscle cells.
• Requires kindlin-2 and beta1-integrin for normal migration and adhesion of vascular smooth muscle cells.
• Involves FAK-dependent regulation of Skp-2 stability and smooth muscle cell proliferation.
• Includes Poldip2 as a negative regulator of matrix synthesis at focal adhesions.
• Relevant to intimal thickening and proliferative vascular disease.
• Provides druggable nodes (PKG, RhoA, Src, ILK) for modulating adhesion.
• Enables CRISPR-based causal testing of candidate negative regulators.
What Happens During negative regulation of smooth muscle cell-matrix adhesion?
Initiation by soluble signals and kinases
In simple terms: A signal tells the smooth muscle cell to loosen its grip on the matrix.
Negative regulation of smooth muscle cell-matrix adhesion is initiated when soluble signals activate kinases such as cGMP-dependent protein kinase (PKG), which reduces pulmonary vascular smooth muscle cell adhesion and migration, an effect modulated by hypoxia. RhoA and Src also selectively regulate cytoskeletal tension and cell-matrix adhesion, providing alternative entry points for negative control.
Integrin and focal adhesion remodeling
In simple terms: The cell rearranges the protein clusters that glue it to the matrix.
Integrin-linked kinase (ILK) regulates cell-matrix contacts and beta-catenin signaling in vascular smooth muscle cells, with implications for intimal thickening. Kindlin-2 regulates migration and adhesion of vascular smooth muscle cells via beta1-integrin, showing that integrin adaptors are central to the adhesion machinery being negatively regulated.
Focal adhesion kinase and proliferation coupling
In simple terms: A kinase at the adhesion site also controls whether the cell divides.
Focal adhesion kinase (FAK)-dependent regulation of S-phase kinase-associated protein-2 (Skp-2) stability provides a mechanism that couples adhesion signaling to smooth muscle cell proliferation, so negative regulation of adhesion can indirectly restrain proliferation.
Matrix synthesis and focal adhesion output
In simple terms: The cell can also reduce the matrix it builds around the adhesion.
Poldip2 negatively regulates matrix synthesis at focal adhesions, adding a matrix-side mechanism by which the adhesion environment can be dampened. Together with kinase and integrin remodeling, this completes the negative regulation defined by GO:2000098.
Key Genes Involved in GO:2000098 negative regulation of smooth muscle cell-matrix adhesion
The following genes and proteins have been experimentally implicated in the regulation of smooth muscle cell-matrix adhesion and its negative control.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PRKG1 (PKG) | cGMP-dependent kinase that reduces pulmonary vascular SMC adhesion and migration | Hypoxia-modulated negative regulator of SMC adhesion |
| RHOA | Selectively regulates cytoskeletal tension and cell-matrix adhesion | Node for tuning adhesion strength |
| SRC | Selectively regulates cytoskeletal tension and cell-matrix adhesion | Kinase target for adhesion modulation |
| ILK | Regulates cell-matrix contacts and beta-catenin signaling in VSMC | Implicated in intimal thickening |
| FERMT2 (Kindlin-2) | Regulates migration and adhesion of vascular SMCs via beta1-integrin | Integrin adaptor in SMC adhesion |
| PTK2 (FAK) | FAK-dependent regulation of Skp-2 stability in SMC proliferation | Couples adhesion to proliferation |
| POLDIP2 | Negatively regulates matrix synthesis at focal adhesions | Matrix-side negative regulator |
| ITGB1 (beta1-integrin) | Required for kindlin-2-mediated SMC migration and adhesion | Core adhesion receptor |
| CTNNB1 (beta-catenin) | Signaling downstream of ILK in VSMC | Links adhesion to transcriptional programs |
| SKP2 | Stability regulated by FAK in SMC proliferation | Connects adhesion to cell-cycle control |
| SQSTM1/p62 | Autophagy-related protein in keratinocyte/fibroblast activation during wound healing | Context for adhesion-related autophagy studies |
| TP53 | p53 in cell invasion, podosomes and invadopodia | Adhesion-structure regulator in invasive cells |
| MAP1LC3B (LC3) | Autophagy marker in keratinocyte activation and wound healing | Readout for autophagy-adhesion crosstalk |
| ATG5 | Core autophagy gene in keratinocyte autophagy and wound healing | Autophagy pathway context |
| ATG7 | Core autophagy gene in keratinocyte autophagy and wound healing | Autophagy pathway context |
| RPTOR (mTORC1 component) | Autophagy-related signaling context in wound healing | Upstream growth-signal context |
| TSC2 | Autophagy-related signaling context in wound healing | Upstream growth-signal context |
How Is negative regulation of smooth muscle cell-matrix adhesion Regulated?
Negative regulation of smooth muscle cell-matrix adhesion is controlled by cGMP/PKG signaling, which suppresses pulmonary vascular SMC adhesion and migration and is itself modulated by hypoxia. RhoA and Src selectively regulate cytoskeletal tension and cell-matrix adhesion, providing additional upstream control. Integrin-linked kinase and beta-catenin signaling regulate cell-matrix contacts in vascular SMCs, while kindlin-2 acts through beta1-integrin to control migration and adhesion. FAK-dependent Skp-2 stability links adhesion signaling to proliferation, and Poldip2 negatively regulates matrix synthesis at focal adhesions. Autophagy-related signaling, including ATG5, ATG7 and LC3, has been linked to keratinocyte and fibroblast activation during wound healing, providing a broader context for adhesion-related remodeling.
negative regulation of smooth muscle cell-matrix adhesion and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ILK | Intimal thickening and vascular remodeling | VSMC knockout and overexpression models |
| FERMT2 (Kindlin-2) | Vascular SMC migration and adhesion via beta1-integrin | Kindlin-2 knockout or knockdown in vascular SMCs |
| PTK2 (FAK) | SMC proliferation via Skp-2 stability | FAK point-mutation and knockout SMC lines |
| POLDIP2 | Matrix synthesis at focal adhesions | Poldip2 knockout and overexpression models |
| PRKG1 (PKG) | Pulmonary vascular SMC adhesion under hypoxia | PKG knockout and hypoxia-exposed SMC models |
Vascular intimal thickening and remodeling
Integrin-linked kinase regulates cell-matrix contacts and beta-catenin signaling in vascular smooth muscle cells, with implications for intimal thickening, a lesion in which excessive SMC adhesion and migration contribute to disease. Kindlin-2-dependent migration and adhesion of vascular smooth muscle cells via beta1-integrin further supports a role for adhesion regulators in vascular remodeling.
Pulmonary vascular disease and hypoxia
cGMP-dependent protein kinase regulates pulmonary vascular smooth muscle cell adhesion and migration, and hypoxia modifies this regulation, linking GO:2000098 to pulmonary vascular pathology.
Proliferative vascular disease
FAK-dependent regulation of Skp-2 stability provides a mechanism by which adhesion signaling controls smooth muscle cell proliferation, a process central to proliferative vascular disease.
Matrix-driven focal adhesion pathology
Poldip2 negatively regulates matrix synthesis at focal adhesions, suggesting that dysregulation of matrix-side control can alter the adhesion microenvironment in vascular disease.
From negative regulation of smooth muscle cell-matrix adhesion-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate gene required for negative regulation of SMC-matrix adhesion? | CRISPR knockout in smooth muscle cell lines |
| Does a specific kinase activity (e.g., FAK) mediate the negative regulation? | Point-mutation knock-in of kinase-dead or phospho-dead alleles |
| Does an adhesion adaptor need a specific binding motif? | Knock-in of binding-site mutants (e.g., kindlin-2/beta1-integrin interface) |
| Where does the protein localize during adhesion turnover? | Tagged knock-in with fluorescent or epitope tags |
| Does excess negative regulator suffice to reduce adhesion? | Overexpression of PKG, Poldip2 or ILK mutants |
| Which pathways cooperate with autophagy in adhesion remodeling? | Knockout of ATG5/ATG7 with adhesion readouts |
How to Study the negative regulation of smooth muscle cell-matrix adhesion Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Cell-matrix adhesion assay | Strength and extent of SMC attachment to matrix | Testing negative regulators such as PKG or kindlin-2 |
| Migration assay | SMC movement after adhesion modulation | Hypoxia and integrin-adaptor studies |
| Focal adhesion imaging | Number, size and dynamics of focal adhesions | RhoA/Src and Poldip2 studies |
| Protein stability assay | Turnover of Skp-2 downstream of FAK | Linking adhesion to proliferation |
| Beta-catenin signaling assay | Transcriptional output downstream of ILK | VSMC intimal thickening models |
| Autophagy marker analysis | LC3, ATG5 and ATG7 activity | Wound-healing and adhesion crosstalk |
| CRISPR knockout screening | Requirement of candidate genes for adhesion control | Causal gene discovery in SMCs |
| Overexpression rescue | Sufficiency of a negative regulator | Testing PKG, ILK or Poldip2 sufficiency |
Adhesion and migration assays
Smooth muscle cell-matrix adhesion and migration can be measured directly in assays used to study PKG, kindlin-2 and ILK function, allowing negative regulation to be quantified under hypoxia or genetic perturbation.
Imaging of focal adhesions and cytoskeleton
Focal adhesion and cytoskeletal tension changes downstream of RhoA and Src can be visualized by imaging, which is central to defining how negative regulation remodels adhesion structures.
Protein stability and signaling analysis
FAK-dependent Skp-2 stability and ILK/beta-catenin signaling are studied by protein-stability and signaling assays, linking adhesion to proliferation and transcription.
Autophagy and wound-healing readouts
Autophagy markers such as LC3 and core genes ATG5 and ATG7 are used in keratinocyte and fibroblast wound-healing models, providing a template for studying adhesion-remodeling crosstalk.
How CRISPR Can Be Used to Study GO:2000098 negative regulation of smooth muscle cell-matrix adhesion
Knockout
CRISPR knockout of candidate genes such as ILK, PTK2 (FAK) or POLDIP2 in smooth muscle cells can test whether they are required for negative regulation of cell-matrix adhesion and downstream proliferation.
Point Mutation
Point-mutation models, for example kinase-dead FAK or phospho-dead variants, can dissect which catalytic or phosphorylation events mediate negative regulation of adhesion.
Knock-in
Knock-in of tagged or binding-site-mutant alleles, such as kindlin-2 or beta1-integrin interface mutants, allows precise mapping of adhesion-adaptor function in smooth muscle cells.
Overexpression
Overexpression of PKG, ILK or Poldip2 can test sufficiency of a candidate negative regulator to reduce smooth muscle cell-matrix adhesion and matrix synthesis.
How EDITGENE Supports negative regulation of smooth muscle cell-matrix adhesion Research
Researchers studying negative regulation of smooth muscle cell-matrix adhesion-related genes often need to determine whether a candidate gene is causally involved in weakening or disassembling integrin-based adhesions, and CRISPR models provide the cleanest way to establish that causality.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of smooth muscle cell-matrix adhesion research.
Frequently Asked Questions About negative regulation of smooth muscle cell-matrix adhesion
What is GO:2000098 negative regulation of smooth muscle cell-matrix adhesion?
It is a biological_process term meaning any process that stops, prevents, or reduces the frequency, rate or extent of smooth muscle cell-matrix adhesion.
What genes are involved in negative regulation of smooth muscle cell-matrix adhesion?
Reported genes and proteins include PRKG1 (PKG), RHOA, SRC, ILK, FERMT2 (kindlin-2), PTK2 (FAK), POLDIP2 and ITGB1.
How is smooth muscle cell-matrix adhesion negatively regulated?
Through kinase signaling such as cGMP/PKG, RhoA/Src tension control, integrin-adaptor remodeling by ILK and kindlin-2, FAK-dependent Skp-2 stability and Poldip2-mediated matrix synthesis control.
Why is negative regulation of smooth muscle cell-matrix adhesion important in disease?
Loss of this brake is linked to intimal thickening, vascular remodeling and proliferative vascular disease.
Does hypoxia affect negative regulation of smooth muscle cell-matrix adhesion?
Yes, hypoxia modulates cGMP-dependent protein kinase regulation of pulmonary vascular smooth muscle cell adhesion and migration.
What role does FAK play in smooth muscle cell adhesion and proliferation?
FAK-dependent regulation of Skp-2 stability provides a mechanism linking adhesion signaling to smooth muscle cell proliferation.
How does kindlin-2 control vascular smooth muscle cell adhesion?
Kindlin-2 regulates migration and adhesion of vascular smooth muscle cells via beta1-integrin.
What is the role of Poldip2 at focal adhesions?
Poldip2 negatively regulates matrix synthesis at focal adhesions.
Which CRISPR models are used to study this process?
Knockout, point-mutation, knock-in and overexpression models in smooth muscle cells are used to test requirement and sufficiency of candidate regulators.
What methods measure negative regulation of smooth muscle cell-matrix adhesion?
Adhesion and migration assays, focal adhesion imaging, protein-stability assays, beta-catenin signaling assays and autophagy marker analysis are commonly used.
Conclusion
GO:2000098, negative regulation of smooth muscle cell-matrix adhesion, defines the processes that weaken or disassemble integrin-based contacts between smooth muscle cells and the extracellular matrix. Experimental evidence implicates cGMP/PKG, RhoA, Src, ILK, kindlin-2, FAK and Poldip2 in this control, with direct relevance to intimal thickening and proliferative vascular disease. CRISPR knockout, point-mutation, knock-in and overexpression models provide the causal toolkit needed to move from correlation to mechanism in this pathway.
References
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