Structure of the KIT protein
The importance of the stem cell factor (SCF)/ KIT signaling pathway in the normal human body is relatively well understood, but the breadth of its oncogenic functions and potential role as a therapeutic target are only just becoming clear.
Agents targeting this pathway have proved more successful in some tumor types than in others; particularly variable has been the role of imatinib (Gleevec, Novartis). More recently, the evolution of a new paradigm of cancer therapy, in which the molecular characteristics of a tumor are used to guide therapeutic regimens for each individual patient, has seemingly brought the story of the SCF/ KIT pathway full circle and is driving increased interest in these agents.
How the Pathway Is Activated
The significant genetic player in this pathway is the KIT
gene, whose KIT protein product is a member of the class III receptor tyrosine kinases (RTKs), a family that includes other receptors such as platelet-derived growth factor receptor (PDGFR). As with other RTKs, the binding of a specific ligand, in this case SCF, leads to receptor dimerization (one receptor molecule binding to another), which activates the intrinsic tyrosine kinase activity of the receptor, leading to its phosphorylation at key amino acid residues.
Schematic of KIT Signaling Pathways
SCF indicates stem cell factor; STAT3, signal transducer and activator of transcription 3; K, tyrosine kinase domain. The MAPK pathway is denoted as RASRAF- MEK-ERK and the PI3K pathway is PI3K-AKT-mTOR.
Adapted from Lovly C, Pao W, Sosman J. KIT in thymic carcinoma: what is KIT? Vanderbilt-Ingram Cancer Center. www.vicc.org. Updated June 30, 2011. Accessed July 25, 2011.
These residues subsequently act as binding sites for signaling molecules within the cell; thus, the process of signal transduction is initiated downstream of the receptor. A number of important downstream signaling cascades are activated by the SCF/KIT pathway including mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling.
Researchers have identified 2 isoforms of the SCF ligand that are quite different in the signaling outcomes they initiate. The isoforms differ in the presence or absence of a proteolytic cleavage site, and their resulting solubility (let’s call them “SCF ” and “SCF-” for simplicity’s sake). SCF initiates a rapid and transient activation of KIT, followed by a rapid degradation, while SCF- leads to a more sustained activation and prolonged downstream signaling.
The SCF/KIT pathway is believed to have a number of major in vivo functions in humans. Like the JAK/STAT pathway described in last month’s “Pathways” article, SCF/KIT signaling is crucial for hematopoiesis, the formation of blood cells. It plays a particularly vital role in the development of primitive hematopoietic cells such as stem and progenitor cells, becoming less important once they have differentiated, such that less than 0.1% of peripheral blood cells express KIT. One important exception is the mast cells, which continue to express KIT at high levels and are dependent on SCF/KIT signaling for their growth, survival, and proper function.
Another important function of the SCF/KIT pathway is in pigmentation, since it has a very well-established role in melanocyte development. Mice with reduced KIT expression have defective pigmentation, and mutations in the KIT
gene have been detected in the majority of humans with piebaldism, a rare inherited condition characterized by a patch of white hair above the forehead.
SCF/KIT signaling is also important in the gastrointestinal tract (specifically in the development of the interstitial cells of Cajal [ICC]), in fertility, and in the nervous system.
Defective SCF/KIT Signaling in Cancer
This myriad of important cellular functions of course translates into a darker side of this pathway, when mutations or altered expression of its component parts lead to the development of cancer.
Unsurprisingly, KIT is associated with several malignant human diseases, which mirror its major in vivo functions, including melanoma, mastocytosis (characterized by an accumulation of mast cells in various tissues), gastrointestinal stromal tumors (GISTs; the most common form of mesenchymal tumor of the digestive tract, thought to arise from the ICC), acute myelogenous lymphoma (AML), and small cell lung carcinoma (SCLC). It also has been described in a range of other tumors such as neuroblastoma, cervical, testicular, thyroid, breast, colon, bladder, renal, pancreatic, and non-small cell lung carcinoma.