The protein known as Cluster of Differentiation 117, or CD117, is a molecule on the surface of many cell types. It is commonly referred to by its alternative name, c-Kit, derived from the \(KIT\) proto-oncogene. CD117 receives external signals that regulate cell growth and survival. While its activities are necessary for normal bodily maintenance, genetic errors affecting this receptor drive several serious diseases. Understanding its normal function and mutated behavior is fundamental to diagnosing and treating these conditions.
Defining CD117 and c-Kit
CD117 is a transmembrane receptor embedded in the cell membrane. It belongs to the class of proteins called receptor tyrosine kinases, which initiate signaling cascades inside the cell upon activation. The protein is coded by the \(KIT\) gene, located on human chromosome 4.
CD117’s structure includes an extracellular, a transmembrane, and an intracellular domain. The extracellular domain binds to its specific signaling molecule, Stem Cell Factor (SCF), also known as kit ligand. When SCF binds, it causes two receptor molecules to pair up, initiating tyrosine kinase activity inside the cell.
This activation triggers chemical reactions that send messages to the cell nucleus, controlling cellular processes. CD117 is expressed on specific, specialized cells throughout the body. These include:
- Hematopoietic stem cells, which form blood cells.
- Mast cells, involved in allergic responses.
- Melanocytes, which produce pigment.
- Germ cells, the precursors to sperm and eggs.
- Interstitial cells of Cajal (ICCs) in the gastrointestinal tract.
The Physiological Functions of CD117
SCF binding to CD117 is necessary for the maintenance and activity of several cell lineages, affecting processes like blood formation and pigmentation. In the bone marrow, CD117 signaling is integral to hematopoiesis, particularly the development and maturation of mast cells. This signaling promotes the survival, proliferation, and differentiation of these immune cells.
CD117 is required for melanogenesis, the process of producing melanin. It supports the migration and survival of melanocytes, the cells responsible for skin and hair color. Disruptions to this pathway can lead to pigment abnormalities, such as patches of unpigmented skin or hair.
The receptor is essential for reproductive health through its involvement in gametogenesis, the formation of mature sperm and egg cells. The \(KIT\) signaling pathway supports the growth and survival of germ cells in the testes and ovaries. In the digestive system, CD117 is expressed by the interstitial cells of Cajal (ICCs), which act as the gut’s pacemaker cells, controlling rhythmic contractions for proper intestinal motility.
CD117 as a Driver of Cancer and Disease
In disease, the CD117 receptor often acquires a mutation that transforms it into a constant growth driver. This change, known as constitutive activation, causes the receptor to signal continuously, even without the Stem Cell Factor ligand. The result is uncontrolled cell proliferation and survival, a hallmark of cancer.
The most well-known example is Gastrointestinal Stromal Tumors (GIST), the most common mesenchymal tumors of the digestive tract. Approximately 85% of GIST cases are driven by an activating mutation in the \(KIT\) gene. These mutations frequently occur in Exon 11, but can also be found in Exons 9, 13, or 17, all resulting in the receptor being permanently activated.
Systemic mastocytosis is driven by a similar mechanism, characterized by the abnormal accumulation of mast cells. Since mast cells naturally express CD117, a gain-of-function mutation in the \(KIT\) gene leads to their unchecked growth. CD117 expression is also a feature of certain subtypes of Acute Myeloid Leukemia (AML) and seminomas, where constant signaling contributes to the proliferation of abnormal cells.
Using CD117 for Diagnostic Identification
Pathologists use CD117 as a diagnostic marker for identifying specific tumors via immunohistochemistry (IHC). This technique involves taking a fixed tissue sample, such as a biopsy, and applying specialized antibodies that bind specifically to the CD117 protein. A visible stain is then applied, allowing the pathologist to confirm the protein’s presence in the tumor cells.
For gastrointestinal tumors, a positive CD117 stain highly indicates a GIST. This step is important because GISTs can be mistaken for other spindle cell tumors, such as leiomyomas or schwannomas, which are typically CD117 negative. Confirming the presence of CD117 guides the patient’s treatment plan. CD117 staining is also used to confirm mast cell disorders and classify certain types of leukemia.
Therapeutic Strategies Targeting CD117
The activated CD117 receptor provided a clear target for drug development, leading to a new class of molecularly directed therapies. These treatments are Tyrosine Kinase Inhibitors (TKIs), which block the abnormal activity of the CD117 protein. The first and most widely used TKI for GIST is Imatinib, marketed under the name Gleevec.
Imatinib functions by fitting into the active site of the CD117 kinase domain, acting as a molecular plug. By occupying this site, the drug prevents the receptor from initiating the internal signaling cascade that drives uncontrolled cell growth. This targeted approach has improved the prognosis for patients with metastatic or unresectable GIST.
Many patients eventually develop resistance to Imatinib due to secondary mutations in the \(KIT\) gene. When this happens, physicians may use second-line TKIs, such as Sunitinib. Sunitinib is a multi-targeted inhibitor that blocks CD117 activity and several other receptors, making it effective against some Imatinib-resistant mutations. The goal is to continuously shut down the growth signal, halting tumor progression and extending patient survival.