KIT proto-oncogene receptor tyrosine kinase
The KIT gene provides instructions for making a protein that belongs to a family of proteins called receptor tyrosine kinases. Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The KIT protein is found in the cell membrane of certain cell types where a specific protein, called stem cell factor, attaches (binds) to it. This binding turns on (activates) the KIT protein, which then activates other proteins inside the cell by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. This process, called phosphorylation, leads to the activation of a series of proteins in multiple signaling pathways.
The signaling pathways stimulated by the KIT protein control many important cellular processes such as cell growth and division (proliferation), survival, and movement (migration). KIT protein signaling is important for the development of certain cell types, including reproductive cells (germ cells), early blood cells (hematopoietic stem cells), immune cells called mast cells, cells in the gastrointestinal tract called interstitial cells of Cajal (ICCs), and cells called melanocytes. Melanocytes produce the pigment melanin, which contributes to hair, eye, and skin color.
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Mutations in the KIT gene are the most common genetic changes associated with gastrointestinal stromal tumors (GISTs). GISTs are a type of tumor that occurs in the gastrointestinal tract, most commonly in the stomach or small intestine. In most cases, these KIT gene mutations are acquired during a person's lifetime and are called somatic mutations. Somatic mutations, which lead to sporadic GISTs, are present only in the tumor cells and are not inherited. Less commonly, KIT gene mutations that increase the risk of developing GISTs are inherited from a parent, which can lead to familial GISTs.
KIT gene mutations associated with GISTs create a protein that no longer requires binding of the stem cell factor protein to be activated. As a result, the KIT protein and the signaling pathways are constantly turned on (constitutively activated), which increases the proliferation and survival of ICCs, leading to GIST formation.
At least 69 KIT gene mutations have been identified in people with piebaldism. This condition is characterized by white patches of skin and hair caused by a lack of melanocytes. The mutations responsible for piebaldism lead to a nonfunctional KIT protein. The loss of KIT signaling is thought to disrupt melanocyte migration and proliferation during development, resulting in patches of skin that lack pigmentation.
Somatic mutations in the KIT gene have been identified in several cancers. KIT gene mutations are involved in some cases of acute myeloid leukemia, which is a cancer of a type of blood cell known as myeloid cells, and sinonasal natural killer/T-cell lymphoma (NKTCL), another blood cell cancer that occurs in the nasal passages. In addition, some people with seminoma, a type of testicular cancer, have a KIT gene mutation. The genetic changes involved in acute myeloid leukemia and seminomas lead to a KIT protein that is constitutively activated. The constant signaling causes overproliferation of the cells that make up these tumors. It is unclear how the KIT mutations in NKTCL are involved in the condition.
KIT gene mutations are also involved in mastocytosis, which represents a group of related conditions. These conditions are characterized by an overgrowth of mast cells, which are cells that trigger inflammation during an allergic reaction or an infection. Accumulation of excess mast cells in the skin causes a condition called urticaria pigmentosa, and accumulation in additional organs leads to systemic mastocytosis. The KIT gene mutations involved in this group of conditions lead to a constitutively activated KIT protein, which causes the overgrowth of mast cells.
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