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 codes for a transmembrane receptor tyrosine kinase (family of receptor tyrosine kinases, which also includes platelet-derived-growth-factor-receptor-alpha) that spans the cell membrane of various cells. This can also occur in soluble form.

The receptor tyrosine kinase (KIT) encoded by the KIT gene 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 classic growth factor receptor and specifically binds the so-called stem cell factor (also known as Kit ligand or mast cell growth factor - see KITLG below).

KIT is physiologically expressed in hematopoietic stem cells, germ cells of the gonads, the interstitial cells of Cajal (intestinal pacemaker cells) and mast cells as well as 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 encoding different isoforms have been found for the KIT gene. Mutations in the KIT gene are associated with gastrointestinal stromal tumors, mast cell diseases, acute myeloid leukemia and piebaldism.

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

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

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

• In addition to GIST, systemic mastocytoses and seminomas are most frequently CD117-positive. However, these neoplasms have mutations in other exons of the KIT gene than GIST and are only partially sensitive to imatinib. However, CD117 expression is not specific for these entities. Other malignant tumors, especially adenoid cystic carcinomas and thymic carcinomas, can also express the protein. Significant (over)expression is found in malignant melanomas of the acrolentiginous type and in mucosal melanomas.
• Furthermore, the encoded c-Kit plays an important role in skin pigmentation, intestinal function and spermatogenesis. C-Kit is expressed in the junctional parts of benign melanocytic nevi of the compound type, but only to a small extent in the dermal parts.
• Mutations in the KIT gene lead to piebaldism, which is characterized by extensive depigmentation and a conspicuous forelock(poliosis). The c-Kit receptor is essential for the migration of melanoblasts from the neural crest. In animals, mutations in the KIT gene lead to leucism (white spottedness)
• KIT mutations play an important role in mastocytosis. This mutation leads to autocrine dysregulation, resulting in increased proliferation, prolonged survival and increased mediator release in the mast cells.
• A mutation in the KIT ligand(KITLG) has been detected in striate and whorled nevoid hypermelanosis (Sorlin A et al. (2017).

Kit mutations:

• Kit-inactivating mutations can lead to fertility disorders in heterozygotes, to piebaldism in humans and to leucism in animals (white spottedness).
• 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 in the active center of the tyrosine kinase lead to autophosphorylation of the tyrosine kinase receptor, with consecutive autostimulation and thus 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.