Researchers Unveil Mechanism to Prevent Cancer by Targeting VEGFR1 Enzyme

Researchers at the Indian Institute of Science Education and Research (IISER), Kolkata, investigated one such RTK called Vascular Endothelial Growth Factor Receptor (VEGFR).

Researchers have decoded the molecular mechanism by which a cell surface receptor, VEGFR1, prevents cancers through autoinhibition in the absence of a ligand, such as hormones. This breakthrough could pave the way for developing medical solutions for colon and renal cancers by using molecules that preferentially stabilize the inactive state of VEGFR1.

Cell surface receptors like Receptor Tyrosine Kinases (RTKs) play a crucial role in converting extracellular signals from chemical cues like growth factors (referred to as ligands) into tightly regulated cellular responses. Ligand binding to extracellular receptors activates intracellular coupled enzymes (tyrosine kinases), which then add phosphate groups to several tyrosine molecules. These molecules function as adaptors for assembling a signaling complex that regulates diverse cellular functions, such as cell growth, development, and immune response. Spontaneous activation of RTKs, in the absence of ligands, is often linked to multiple human pathologies like cancers, diabetes, and autoimmune disorders.

Researchers at the Indian Institute of Science Education and Research (IISER), Kolkata, investigated one such RTK called Vascular Endothelial Growth Factor Receptor (VEGFR). The VEGFR family of receptors is the key regulator of the process of generating new blood vessels, essential for functions like embryonic development, wound healing, tissue regeneration, and tumor formation. Targeting VEGFRs can treat various malignant and non-malignant diseases.

The researchers focused on the different behaviors of two members of the VEGFR family: VEGFR1 and VEGFR2. While VEGFR2, the primary receptor regulating new blood vessel formation, can be spontaneously activated without its ligand, VEGFR1 cannot be spontaneously activated even when overexpressed in cells. VEGFR1 camouflages as a dead enzyme and binds with ten-fold higher affinity to its ligand VEGF-A than VEGFR2, leading to transient kinase activation.

Activation of VEGFR1 has been linked to cancer-associated pain, tumor cell survival in breast cancer, and migration of human colorectal cancer cells. Dr. Rahul Das and his team from IISER Kolkata discovered that a unique ionic latch, present only in VEGFR1, keeps the kinase autoinhibited in the basal state. This ionic latch hooks the juxtamembrane segment onto the kinase domain, stabilizing the autoinhibited conformation of VEGFR1.

The researchers proposed a crucial role for cellular tyrosine phosphatase in modulating VEGFR1 activity. Their research, conducted at the Analytical Biology Facility at IISER Kolkata with its DST-FIST supported ITC and stopped-flow fluorimeter, highlighted the therapeutic potential of phosphatase modulators in regulating VEGFR1-mediated pathological angiogenesis (formation of new blood vessels), which occurs in cancer.

Published in the journal Nature Communications, this discovery may open new avenues for developing therapeutic interventions against pathological conditions due to the spontaneous activation of VEGFR signaling. Small molecules targeting the autoinhibited state of VEGFR1 hold significant potential for treating cancers like human colorectal carcinoma and renal cancer, where VEGFR1 is overexpressed.