Rtk

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Cell typesa

Implicated diseases

SCF receptor

VEGF receptors

Hematopoietic stem cells

Melanocytes

Germ cells

Interstitial cells of Cajal Neural cells Mast cells

Vascular endothelial cells Lymphatic endothelial cells Monocytes and macrophages Smooth muscle cells

Cancer

Mast cell diseases Angiogenesis

Cancer Inflammation

Cardiovascular acute myelogenous leukemia, chronic myelogenous leukemia small cell lung cancer seminoma gastrointestinal stromal tumors central nervous system tumors mastocytosis asthma and allergy tumor growth and metastasis rheumatoid arthritis psoriasis ocular diseases acute myelogenous leukemia

Kaposi's sarcoma inflammatory bowel disease

HIV-associated dementia sarcoidosis rheumatoid arthritis allergy and asthma atherosclerosis restenosis aThe normal cell types in which the receptor has been observed to be expressed and mediate a biological function.

Figure 1 Structural motifs characteristic of SCF and VEGF receptors. The receptor for SCF is related to the RTK for PDGF and CSF-1 containing five immunoglobulin motifs in the extracellular domain and a cytoplasmic kinase containing a long nonki-nase region insert (''split kinase''). The receptors for VEGF ligands contain seven immunoglobulin domains in the extracellular domain.

Figure 1 Structural motifs characteristic of SCF and VEGF receptors. The receptor for SCF is related to the RTK for PDGF and CSF-1 containing five immunoglobulin motifs in the extracellular domain and a cytoplasmic kinase containing a long nonki-nase region insert (''split kinase''). The receptors for VEGF ligands contain seven immunoglobulin domains in the extracellular domain.

at the W locus (W mice) have characteristic white spots on their abdomen resulting from lack of skin pigmentation. W mice exhibit other abnormalities, including reproductive difficulties associated with abnormal germ cell development, diminished numbers of tissue mast cells, and macrocytic anemia resulting from defective hematopoiesis. These observations provide genetic evidence for the critical role of c-kit in the development of melanocytes and mast, germ, and hematopoietic cells.

Mice exhibiting the Steel (Sl) mutation have a very similar phenotype as those with W mutations. However, the Sl locus was found to map to mouse chromosome 10, indicating that the defect resulted from mutation of a protein other than c-kit and suggesting that this locus may encode the ligand for this receptor. Cloning of the cDNA for the ligand of c-kit (Huang et al., 1990; Martin et al., 1990; Williams et al., 1990) enabled the subsequent confirmation of this hypothesis. The protein encoded by the Sl locus has been called kit ligand (KL), stem cell factor (SCF), or mast cell growth factor (MGF) based on its biological properties used to identify it (see reviews). For simplicity, we will use SCF to designate the ligand for the c-kit RTK. SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 D, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form a soluble, glycosylated protein which noncovalently dimerizes. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. However, there have been reports indicating that the soluble and membrane-associated forms may induce somewhat different biological responses (Miyazawa et al., 1995; Williams 1997). Under normal circumstances, SCF typically activates c-kit by a paracrine mechanism. For example, in the skin, SCF is predominantly expressed by fibroblasts, kera-tinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit-expressing stem cells (Fig. 2). In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the intersti-

Figure 2 Paracrine mechanisms by which SCF, FL, and VEGF activate their RTK. SCF is produced as an active transmembrane protein capable of receptor activation, which can be proteolytically cleaved to form a soluble dimer that retains biological activity for activation of c-kit. VEGF and related ligands are synthesized as soluble proteins that dimerize and activate various VEGF receptors. Some splice variants contain motifs that enable them to interact with heparin sulfate proteoglycans on the surface of cells or in the extracelluar matrix. Some splice variants can also bind to the accessory receptor, neuropilin-1.

Figure 2 Paracrine mechanisms by which SCF, FL, and VEGF activate their RTK. SCF is produced as an active transmembrane protein capable of receptor activation, which can be proteolytically cleaved to form a soluble dimer that retains biological activity for activation of c-kit. VEGF and related ligands are synthesized as soluble proteins that dimerize and activate various VEGF receptors. Some splice variants contain motifs that enable them to interact with heparin sulfate proteoglycans on the surface of cells or in the extracelluar matrix. Some splice variants can also bind to the accessory receptor, neuropilin-1.

tial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF, which regulates spermatogenesis by interaction with c-kit on germ cells.

In mice, a variety of mutations have been identified that inactivate c-kit RTK activity leading to the W phenotype. In addition, several mutations of c-kit have also been identified that lead to the constitutive activation of c-kit kinase and development of cell-specific pathologies. In addition to mutations, c-kit can be incorrectly activated by aberrant expression or processing of either the receptor (e.g., overexpression) or ligand (e.g., formation of an autocrine loop or excessive soluble SCF). A wide variety of diseases have been associated with aberrant activation of the c-kit RTK.

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