KDR - kinase insert domain receptor | Elisa - Clia - Antibody - Protein

Background

KDR, also known as vascular endothelial growth factor receptor 2 (VEGFR-2), is a critical protein in the regulation of angiogenesis and vascular development. This receptor tyrosine kinase (RTK) is encoded by the KDR gene located on chromosome 4q12 in humans. KDR is a member of the VEGF receptor family, which plays an essential role in the processes of vasculogenesis and angiogenesis by mediating the cellular responses to the vascular endothelial growth factor (VEGF). The VEGF family consists of several ligands, with VEGF-A being the primary ligand for KDR.

KDR is predominantly expressed in endothelial cells, where it regulates vascular permeability, endothelial cell proliferation, migration, and survival. Due to its pivotal role in vascular biology, KDR has been extensively studied in the context of cancer, where angiogenesis is a crucial process for tumor growth and metastasis. KDR's involvement in pathological angiogenesis makes it a significant target for anti-angiogenic therapies in cancer treatment. Moreover, it has implications in other diseases characterized by abnormal vascular growth, such as age-related macular degeneration and rheumatoid arthritis.

Protein Structure

KDR is a large transmembrane protein with a complex structure that facilitates its role as a receptor tyrosine kinase. The structure of KDR includes:

1. Extracellular Domain: The extracellular region of KDR is composed of seven immunoglobulin (Ig)-like domains. These domains are responsible for ligand binding, primarily to VEGF-A. The interaction between VEGF-A and the extracellular domain of KDR triggers receptor dimerization and subsequent activation.
2. Transmembrane Domain: This single-pass transmembrane segment anchors KDR to the cell membrane and transmits conformational changes from the extracellular domain to the intracellular region upon ligand binding.
3. Intracellular Domain: The intracellular region contains the tyrosine kinase domain, which is interrupted by a kinase insert domain, characteristic of the KDR family. This domain is critical for the autophosphorylation of tyrosine residues, which activates downstream signaling pathways.
4. Juxtamembrane Domain: This segment, located just inside the cell membrane, plays a role in modulating receptor activation and kinase activity.

The specific structure of KDR, with its multiple domains, enables precise control over its activity and the initiation of multiple downstream signaling cascades upon activation.

Classification and Subtypes

KDR belongs to the class of receptor tyrosine kinases (RTKs) and more specifically to the type III RTKs, which also include receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF). The VEGF receptor family consists of three main receptors: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Among these, VEGFR-2 (KDR) is the principal mediator of the angiogenic effects of VEGF.

While KDR itself does not have subtypes, its activity can be modulated by different splice variants of VEGF ligands and co-receptors such as neuropilins (NRP-1 and NRP-2). These variations can influence the binding affinity, signaling outcomes, and biological effects of the receptor.

Function and Biological Significance

KDR functions as a critical regulator of endothelial cell function and vascular biology. Its main roles include:

1. Angiogenesis: KDR is the primary mediator of VEGF-induced angiogenesis. It promotes endothelial cell proliferation, migration, and new blood vessel formation, which are essential processes in both normal physiology and pathological conditions such as tumor growth.
2. Vascular Permeability: KDR activation increases vascular permeability, allowing for the passage of nutrients and immune cells into tissues. This function is crucial during inflammation and wound healing.
3. Endothelial Cell Survival: KDR signaling pathways promote the survival of endothelial cells, protecting them from apoptosis under stress conditions.
4. Hemangioblast Differentiation: KDR plays a role in the differentiation of hemangioblasts into endothelial and hematopoietic lineages during embryonic development.
5. Lymphangiogenesis: Although primarily involved in angiogenesis, KDR also has roles in lymphatic vessel formation through its interaction with VEGF-C and VEGF-D.

Clinical Issues

Dysregulation of KDR has significant clinical implications:

1. Cancer: Overexpression or hyperactivation of KDR is associated with increased tumor angiogenesis, contributing to tumor growth and metastasis. As a result, KDR is a major target for anti-angiogenic therapies in oncology. Drugs like bevacizumab (a monoclonal antibody against VEGF) and tyrosine kinase inhibitors (TKIs) such as sunitinib and sorafenib inhibit KDR signaling, thereby reducing tumor vascularization.
2. Ocular Diseases: Abnormal KDR signaling is implicated in diseases like age-related macular degeneration (AMD) and diabetic retinopathy, where pathological angiogenesis leads to vision loss. Anti-VEGF therapies targeting KDR pathways are effective treatments for these conditions.
3. Cardiovascular Diseases: KDR plays a role in the maintenance of vascular homeostasis, and its dysregulation can contribute to cardiovascular pathologies, including atherosclerosis and hypertension.
4. Inflammatory Diseases: KDR-mediated vascular permeability and angiogenesis can exacerbate conditions like rheumatoid arthritis and inflammatory bowel disease, where excessive blood vessel formation and inflammation are problematic.

Summary

KDR, or VEGFR-2, is a pivotal receptor tyrosine kinase involved in regulating angiogenesis and vascular function. Its complex structure, featuring extracellular ligand-binding domains, a transmembrane segment, and an intracellular kinase domain, enables it to mediate the effects of VEGF on endothelial cells. KDR is critical for angiogenesis, vascular permeability, and endothelial cell survival, playing essential roles in both normal physiological processes and various diseases.

Dysregulation of KDR is implicated in cancer, ocular diseases, cardiovascular conditions, and inflammatory disorders. Therapeutic targeting of KDR with anti-angiogenic drugs and VEGF inhibitors has proven effective in treating several of these conditions. Continued research into KDR's mechanisms and interactions holds promise for developing novel therapies to modulate angiogenesis and treat related diseases effectively.