KIT gene

The KIT gene was originally identified as a homolog of the feline sarcoma virus oncogene v-kit and is often referred to as the proto-oncogene or c-kit. The kit gene is located on chromosome 4, gene locus q11-q12 and encodes a cell membrane-spanning (transmembrane) receptor tyrosine kinase (family of receptor tyrosine kinases, which includes platelet-derived-growth-factor-receptor-alpha). This can also occur in soluble form.

The receptor tyrosine kinase encoded by KIT-GEn has an N-terminal extracellular region with five immunoglobulin-like domains, a transmembrane region and an intracellular tyrosine kinase domain at the C-terminus. The Kit protein is a classical growth factor receptor and specifically binds the so-called stem cell factor (also Kit ligand or mast cell growth factor). KIT is physiologically expressed in hematopoietic stem cells, germ cells of the gonads, the interstitial cells of Cajal (intestinal pacemaker cells) and mast cells, and melanocytes. Kit-mediated signal transduction regulates proliferation, differentiation, and apoptosis and plays a role in gametogenesis, hematopoiesis, mast cell development, melanogenesis, and Cajal cell development.
The KIT gene is a protooncogene (precursor of a potentially cancer-causing gene product). Several transcript variants have been found for the KIT gene, encoding different isoforms. Mutations in the KIT gene are associated with gastrointestinal stromal tumors, mast cell disease, acute myeloid leukemia, and Piebaldism.

• The C-KIT gene product (also c-Kit, CD 117- see also CD classification) is found mainly in hematopoietic stem cells but also in multipotent and myeloid progenitor cells. It is activated by its ligand (=stem cell factor).

• Kit is essential for proliferation and differentiation of stem cells (hematopoiesis, angiogenesis).

• Of outstanding diagnostic importance is the detection of c-Kit expression in gastrointestinal stromal tumors (GIST). Approximately 95% of all GIST are immunohistochemically CD117 positive. The vast majority of all other sarcomas as well as carcinomas and also lymphomas are CD117 negative, so this marker has very good sensitivity and specificity for the diagnosis of GIST.

• Besides GIST, systemic mastocytoses as well as seminomas are most frequently CD117 positive. However, these neoplasms have mutations in other exons of the Kit gene than GIST and are only partially imatinib sensitive. CD117 expression is not specific to these entities, however. Other malignant tumors, especially adenoid cystic carcinomas, tymus carcinomas may also express the protein. Distinct (over)expressions are found in malignant melanomas of the acrolentiginous type and in mucinous melanomas.
• Furthermore, c-Kit plays a significant role in skin pigmentation, intestinal function and spermatogenesis. C-Kit is expressed in the junctional portions of benign compound-type melanocytic nevi, and to a lesser extent in the dermal portions.
• KIT mutations play a significant role in mastocytoses. This mutation causes autocrine dysregulation, resulting in increased proliferation, prolonged survival, and enhanced mediator release in mast cells.
• A mutation in KIT ligand (KITLG) has been demonstrated in striate and whorl nevoid hypermelanosis (Sorlin A et al. (2017).

Kit mutations:

• Kit-inactivating mutations can lead to fertility disorders in heterozygotes, to piebalism (leucism) as well as to cheating (horses/cows) in animals.
• Kit-activating mutations can lead to a gain of function, e.g. to a stem cell factor-independent proliferation of mast cells (point mutations of the kit gene are detected in some systemic mastocytoses ).

Resulting conformational changes of the active centre of the tyrosine kinase lead to autophosphorylation of the tyrosine kinase receptor, with consecutive autostimulation and thereby to ligand-independent cell proliferation.

1. Horny HP et al (2008) Mastocytosis. German medical journal 40: 686-692
2. Pillomi L et al (2011) The usefulness of c-Kit in the immunohistochemical assessment of melanocytic lesions. Eur J Histochem 55:e20
3. Sorlin A et al (2017) Mosaicism for a KITLG mutation in Linear and Whorled Nevoid Hypermelanosis.
   J Invest Dermatol 137:1575-1578.
4. Yarden Y et al (1987) Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO Journal 6: 3341-3351.