Camouflaging as a Dead Enzyme: VEGFR1 Holds Key to Medical Solutions for Colon and Renal Cancers

Researchers at the Indian Institute of Science Education and Research (IISER), Kolkata, have decoded the molecular mechanism of VEGFR1, a cell surface receptor, and its role in preventing cancers. This discovery offers potential medical solutions for colon and renal cancers by stabilizing the inactive state of VEGFR1.

VEGFR1 and its Mechanism:

• Introduction to the Enzyme: VEGFR1 is part of the family of enzymes known as Receptor Tyrosine Kinases (RTK), which are crucial for converting extracellular signals into cellular responses. VEGFR1 remains autoinhibited in the absence of a ligand.
• Role in Cellular Functions: RTKs, including VEGFR1, regulate cell differentiation, proliferation, survival, metabolism, and migration. Activation of these receptors leads to the formation of a signalling complex that controls diverse cellular functions.
• Autoinhibition and Pathology: Spontaneous activation of RTKs, in the absence of ligands, is associated with various human pathologies, including cancers. Researchers are exploring how cells maintain the autoinhibited state of these enzymes and why autoinhibition is breached in diseases.

VEGFR1’s Unique Behavior and Therapeutic Potential:

• Differential Activation: Among the VEGFR family, VEGFR1 cannot be spontaneously activated even when overexpressed, unlike VEGFR2, which can activate without its ligand. VEGFR1 binds with ten-fold higher affinity to its ligand VEGF-A, inducing transient kinase activation.
• Cancer Associations: Activation of VEGFR1 is linked to cancer-associated pain, tumor cell survival in breast cancer, and migration of colorectal cancer cells.
• Ionic Latch Mechanism: A unique ionic latch present only in VEGFR1 keeps the kinase autoinhibited. This latch hooks the juxtamembrane segment onto the kinase domain, stabilizing the autoinhibited state.

Implications for Cancer Treatment:

• Therapeutic Modulation: The research proposes the role of cellular tyrosine phosphatase in modulating VEGFR1 activity, highlighting the therapeutic potential of phosphatase modulators in regulating pathological angiogenesis.
• Research and Discoveries: The research, conducted using advanced facilities at IISER Kolkata and published in Nature Communications, underscores the potential of small molecules targeting the autoinhibited state of VEGFR1 for treating cancers such as colorectal carcinoma and renal cancer.
• Future Directions: This discovery opens avenues for developing therapeutic interventions against diseases caused by spontaneous VEGFR signalling activation, particularly in cancers where VEGFR1 is overexpressed.

UPSC Mains Questions:

Q. Explain the significance of cell surface receptors like VEGFR1 in the development of new medical treatments for cancer. How can understanding their mechanisms contribute to advancements in healthcare?