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Camouflaging as a dead enzyme VEGFR1 holds key to medical solutions for colon and renal cancers
Context:
Researchers at the Indian Institute of Science Education and Research (IISER), Kolkata, have decoded the molecular mechanism of VEGFR1,a cell surface receptor from the RTK family, which prevents cancers by regulating various cellular functions
What are VEGF Receptors and their Functions:
- VEGF receptors are membrane proteins that link sensing of circulating ligands to complex signal transduction outcomes, regulating cell and tissue function.
- These receptors regulate the development of biological tubes controlling the vascular and lymphatic networks.
What are Enzymes?
- Enzymes are biologically active proteins found everywhere in nature.
- When one substance needs to be transformed into another, nature uses enzymes to speed up and control the process. This is called catalysis, so enzymes are catalysts..
Decoding the Molecular Mechanism of VEGFR1:
- VEGFR1 remains autoinhibited without a ligand, indicating potential treatments for colon and renal cancers by stabilising its inactive state. Receptor Tyrosine Kinases (RTK) convert extracellular signals from ligands into regulated cellular responses.
- Extracellular molecules are critical regulators of physiology and development in organisms.
- There are many different types of signals including peptides, small lipophilic molecules, small hydrophilic molecules and gases.
- Ligand binding activates intracellular tyrosine kinases, which phosphorylate tyrosine residues, forming a signalling complex for cell growth, development, and immune response.
- Spontaneous RTK activation without ligands is linked to pathologies like cancers, diabetes, and autoimmune disorders.
- VEGFRs regulate new blood vessel generation, essential for embryonic development, wound healing, tissue regeneration, and tumour formation.
- Targeting VEGFRs can treat various malignant and non-malignant diseases.
Difference between VEGFR1 and VEGFR2:
- Both are part of the same receptor family.
- VEGFR2, the primary receptor for new blood vessel formation, can be spontaneously activated without a ligand.
- VEGFR1 cannot be spontaneously activated even when overexpressed in cells.
- VEGFR1 binds with ten-fold higher affinity to its ligand VEGF-A than VEGFR2, inducing transient kinase activation.
Unique Mechanism of VEGFR1 in Cancer Prevention and Therapeutic Potential:
- Cancer-Associated Effects: Activation of VEGFR1 leads to cancer-associated pain, tumour cell survival in breast cancer, and migration of colorectal cancer cells.
- A unique ionic latch in VEGFR1 keeps the kinase autoinhibited by hooking the juxtamembrane segment onto the kinase domain, stabilising its inactive state.
- Cellular tyrosine phosphatase crucially modulates VEGFR1 activity.
- The research highlighted the therapeutic potential of phosphatase modulators in regulating VEGFR1-mediated pathological angiogenesis in cancer.
Do You Know?
- Colon cancer is defined as cells growing in the colon, which is the initial and longest segment of the large intestine.
- Renal cell cancer, also known as kidney cancer or renal cell adenocarcinoma, involves malignant cells found in the lining of very small tubes (tubules) within the kidney.