KIT - KIT receptor tyrosine kinase ( proto oncogene) | Elisa - Clia - Antibody - Protein

Background

The KIT protein, also known as the KIT receptor tyrosine kinase or CD117, is a proto-oncogene that encodes a transmembrane receptor. It plays essential roles in cell growth, survival, migration, and differentiation in several types of cells, especially in hematopoietic stem cells, germ cells, melanocytes, and cells in the gastrointestinal tract. The gene encoding KIT is located on chromosome 4q12 and is highly conserved across species, highlighting its fundamental role in development and cellular homeostasis.

KIT is activated by binding to its ligand, stem cell factor (SCF), also known as mast cell growth factor. This binding triggers a cascade of downstream signaling pathways critical for normal cellular processes. However, mutations in KIT can result in its constitutive activation, which is implicated in various diseases, including gastrointestinal stromal tumors (GISTs), systemic mastocytosis, acute myeloid leukemia (AML), and other cancers. As a proto-oncogene, KIT’s aberrant signaling due to mutation can drive tumorigenesis, making it a target for cancer therapies, particularly tyrosine kinase inhibitors (TKIs).

Protein Structure

KIT is a transmembrane glycoprotein with a complex structure that enables its function as a receptor tyrosine kinase. The structure of KIT can be divided into four main domains:

Extracellular Domain:

• The extracellular region of KIT consists of five immunoglobulin-like (Ig-like) domains that play a critical role in ligand binding.
• Upon binding SCF, the receptor dimerizes, which is essential for activating its tyrosine kinase activity. These Ig-like domains undergo conformational changes upon ligand binding, facilitating receptor dimerization and activation.

Transmembrane Domain:

• KIT contains a single α-helical transmembrane domain spanning the plasma membrane. This domain stabilizes the receptor in the membrane and aids in the propagation of the dimerization signal across the membrane.
• The transmembrane domain ensures that dimerization, initiated by extracellular ligand binding, leads to the proper juxtaposition of intracellular domains for signal transduction.

Juxtamembrane Domain:

• The juxtamembrane domain acts as a regulatory region, controlling the activity of the kinase domain. This segment typically suppresses kinase activity in the absence of ligand binding.
• Mutations in this domain, especially in exon 11, are common in cancers such as GIST and lead to constitutive activation of KIT, independent of SCF binding.

Intracellular Kinase Domain:

• The intracellular segment contains the kinase domain, divided into two subdomains, essential for its enzymatic activity. The kinase domain includes an ATP-binding pocket and catalyzes the phosphorylation of tyrosine residues on KIT itself (autophosphorylation) and downstream proteins, which is crucial for signaling.
• The activation loop within the kinase domain undergoes conformational shifts upon ligand binding and dimerization, allowing for autophosphorylation of key tyrosine residues. These phosphorylated tyrosines then recruit various adapter proteins, triggering multiple downstream signaling pathways.

Classification and Subtypes

KIT belongs to the type III receptor tyrosine kinase family, which includes receptors like the platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R), and FLT3. These receptors are characterized by similar domain structures, including immunoglobulin-like domains in their extracellular regions, and all play roles in cellular growth and differentiation.

KIT mutations often occur in specific exons associated with different cancer types:

• Exon 11 Mutations: Common in GIST, leading to constitutive receptor activation.
• Exon 17 Mutations: Found in systemic mastocytosis and often associated with resistance to first-generation TKIs.
• Exons 9 and 13 Mutations: Present in other cancers, each contributing differently to aberrant signaling and drug resistance.

Function and Biological Significance

KIT’s function is primarily to mediate the effects of stem cell factor (SCF), impacting various physiological processes:

Hematopoiesis:

• KIT is critical in hematopoiesis, particularly in the self-renewal and differentiation of hematopoietic stem cells (HSCs) in the bone marrow. Binding of SCF to KIT activates pathways necessary for the proliferation and survival of these progenitor cells, allowing for the generation of all blood cell types.

Mast Cell Development:

• KIT is indispensable for mast cell proliferation and maturation. In tissues, SCF-KIT signaling influences the differentiation and expansion of mast cells, which are vital in immune responses and allergic reactions.

Germ Cell Development:

• KIT signaling is essential for the migration, survival, and proliferation of primordial germ cells, impacting fertility. Deficiencies or mutations in KIT signaling pathways can lead to infertility or impaired gametogenesis.

Pigmentation:

• KIT is involved in melanocyte development and function, where SCF-KIT signaling promotes survival and proliferation of melanocytes, the cells responsible for pigmentation. Loss of KIT function in this context can lead to pigmentation disorders.

Neurogenesis:

• KIT also has roles in neural development, particularly in the differentiation of neural crest-derived cells, which give rise to a variety of cell types in the peripheral nervous system.

Wound Healing and Angiogenesis:

• KIT signaling plays a role in tissue repair and regeneration by regulating cellular proliferation and migration during wound healing. In endothelial cells, it contributes to the formation of new blood vessels (angiogenesis), particularly under hypoxic conditions.

Clinical Issues

Abnormal KIT signaling, often due to mutations, is associated with several diseases:

Gastrointestinal Stromal Tumors (GIST):

• KIT mutations are a hallmark of GIST, with about 80% of cases exhibiting activating mutations, primarily in exon 11. These mutations cause continuous activation of KIT without SCF binding, leading to uncontrolled cellular proliferation.
• Imatinib, a tyrosine kinase inhibitor, is often used to treat GIST, especially in cases with exon 11 mutations. However, mutations in exons 13 and 17 can confer resistance, necessitating alternative therapies like sunitinib and regorafenib.

Systemic Mastocytosis:

• KIT mutations, especially the D816V mutation in exon 17, are frequently found in systemic mastocytosis, a disorder characterized by the abnormal accumulation of mast cells. This mutation causes resistance to imatinib, complicating treatment.
• Newer TKIs, such as midostaurin, have shown effectiveness against D816V-mutant KIT in mastocytosis.

Acute Myeloid Leukemia (AML):

• KIT mutations can also contribute to AML pathogenesis, particularly in subtypes with core-binding factor translocations. These mutations result in enhanced proliferation and survival of leukemic cells.
• AML with KIT mutations may be less responsive to conventional chemotherapy, making TKIs a potential therapeutic option for certain cases.

Melanoma and Other Cancers:

• KIT mutations and overexpression are also found in melanoma and certain other cancers, especially mucosal and acral melanomas. Here, KIT acts as an oncogenic driver, promoting cancer cell survival and invasion.
• KIT inhibitors are being explored for treatment in KIT-mutant melanoma, though resistance often limits their long-term efficacy.

Summary

KIT, encoded by the KIT gene, is a receptor tyrosine kinase with significant roles in hematopoiesis, immune function, pigmentation, and cell survival across various tissues. Structurally, KIT comprises an extracellular domain for ligand binding, a transmembrane domain for structural stability, a regulatory juxtamembrane region, and an intracellular tyrosine kinase domain for signal transduction. KIT primarily interacts with stem cell factor (SCF) to regulate cell proliferation, differentiation, and survival, impacting cell types such as hematopoietic stem cells, mast cells, and melanocytes.

Mutations in KIT, especially in exons 11 and 17, are implicated in cancer progression and other pathologies, including GIST, systemic mastocytosis, and AML. These mutations lead to constitutive activation of the kinase and uncontrolled cell growth, driving tumorigenesis. Due to its role in various cancers, KIT has become a key target for tyrosine kinase inhibitors like imatinib, although resistance due to additional mutations is common. KIT’s function as a proto-oncogene and therapeutic target makes it a significant focus in cancer research and treatment strategies.