RAP1A Human
Description
Angiogenesis and Endothelial Function
RAP1A regulates angiogenesis by modulating endothelial cell adhesion, migration, and tube formation. Key findings include:
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FGF2 Response: Rap1a−/− mice show impaired angiogenesis in response to fibroblast growth factor 2 (FGF2), with defective aortic ring sprouting and reduced extracellular signal-regulated kinase (ERK) activation .
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Integrin Activation: RAP1A enhances β1/β3 integrin activation, promoting cell adhesion and migration. Knockdown in human microvascular endothelial cells (HMVECs) reduces adhesion to extracellular matrices and increases vascular permeability .
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VEGFR2 Signaling: RAP1A and its paralog, RAP1B, synergistically activate VEGF receptor 2 (VEGFR2), a critical regulator of vascular endothelial growth factor (VEGF)-mediated angiogenesis .
| Parameter | Rap1a−/− Mice Phenotype | Rap1b−/− Mice Phenotype |
|---|---|---|
| FGF2-induced sprouting | Absent | Partially impaired |
| ERK/p38 activation | Reduced | Reduced |
| VEGFR2 activation | Not directly studied | Impaired kinase activity |
Calcium Signaling and Endothelial Barrier Function
RAP1A modulates store-operated calcium entry (SOCE) in endothelial cells:
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Orai1 Regulation: siRNA knockdown of RAP1A increases Orai1 channel expression and SOCE, leading to enhanced nuclear factor of activated T-cells (NFAT) activation and proinflammatory cytokine production (e.g., IL-6, CXCL1) .
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In Vivo Implications: EC-specific Rap1A knockout mice exhibit pulmonary edema, elevated lung permeability, and increased Orai1 expression. Targeting Orai1 with siRNA reverses these effects .
| Experimental Condition | SOCE (ATP/Thapsigargin) | Orai1 Expression | Inflammation |
|---|---|---|---|
| siControl ECs | Basal | Normal | Low |
| siRap1A ECs | ↑ 2–3× | ↑ 2–3× | ↑ (IL-6, CXCL1, CCL5) |
| siRap1A + siOrai1 ECs | Normalized | Normalized | ↓ |
Telomere Regulation
RAP1A interacts with telomeric proteins (e.g., TRF2) to regulate telomere length and heterogeneity:
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Negative Regulator: Overexpression of RAP1A inhibits telomere elongation, while mutants lacking the BRCT or Myb domains induce telomere elongation .
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Heterogeneity Control: RAP1A deficiency reduces telomere length variability, suggesting a role in stabilizing telomere length distribution .
| RAP1A Mutant | Telomere Length | Heterogeneity | Mechanism |
|---|---|---|---|
| ΔBRCT | ↑ | ↓ | Disrupted protein interactions |
| ΔMyb | ↑ | ↑ | Impaired TRF2 binding |
| ΔC | ↑ | Not localized | Loss of telomere binding |
Metabolic Regulation in Pancreatic β-Cells
Proteomic studies in Rap1a−/− mice reveal altered glucose metabolism:
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Insulin Secretion: Rap1A-deficient islets show reduced insulin release in response to high glucose, linked to impaired Epac2-Rap1A signaling .
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Protein Expression: Differentially expressed proteins include Ero1β (protein folding) and Tpi1 (glycolysis), suggesting disrupted β-cell function .
| Protein | Function | Expression in Rap1a−/− | Pathway Affected |
|---|---|---|---|
| Ero1β | Protein disulfide isomerase | ↓ | ER stress response |
| Tpi1 | Glycolysis enzyme | ↓ | Carbohydrate metabolism |
Interactions and Signaling Pathways
RAP1A interacts with multiple effector proteins and signaling molecules:
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C-Raf/Raf Kinases: Competes with Ras for binding to RAF, modulating ERK activation .
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Integrins: Promotes αLβ2 (LFA-1) and β1 integrin activation via inside-out signaling .
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Epac/RapGEFs: Activated by cAMP analogs (e.g., 8CPT-cAMP), triggering B-Raf→MEK→ERK and Akt pathways .
Therapeutic and Research Implications
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Angiogenesis: RAP1A inhibitors could target pathologic angiogenesis in cancer, while activators might enhance wound healing .
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Inflammatory Disorders: Targeting RAP1A-Orai1 axis may reduce endothelial permeability in pulmonary edema or acute lung injury .
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Diabetes: Enhancing Rap1A-Epac2 signaling in β-cells could improve insulin secretion in metabolic disorders .
Product Specs
Product Science Overview
The RAP1A gene is located on chromosome 1 at the position 1p13.2 . The protein encoded by this gene shares approximately 50% amino acid identity with the classical RAS proteins and has numerous structural features in common . The protein undergoes a change in conformational state and activity depending on whether it is bound to GTP or GDP .
RAP1A plays a crucial role in various biological processes, including cell proliferation, adhesion, spreading, migration, and cancer progression . It is activated by several types of guanine nucleotide exchange factors (GEFs) and inactivated by two groups of GTPase-activating proteins (GAPs) . The activation status of RAP1A is therefore affected by the balance of intracellular levels of GEFs and GAPs .
Some of the key biological processes involving RAP1A include:
- Establishment of endothelial barrier
- Regulation of cell junction assembly
- Positive regulation of glucose import
- Microvillus assembly
- Regulation of insulin secretion
- Small GTPase mediated signal transduction
- Nervous system development
- Liver regeneration
- Protein transport
- Response to antineoplastic agents
RAP1A has been implicated in tumor malignancy due to its role in regulating signaling pathways that affect cell proliferation and adhesion . It is associated with various cancers, including lung cancer, breast cancer, and thyroid cancer . The protein’s ability to regulate cell adhesion and migration makes it a significant player in cancer progression and metastasis.
Research on RAP1A has shown its involvement in osteoblastic differentiation via the ERK and p38 signaling pathways . This highlights its potential as a therapeutic target in bone-related diseases and cancer. Additionally, alternative splicing of the RAP1A gene results in multiple transcript variants, which may have different functional implications .
