gastrointestinal stromal tumor Mutations in the PDGFRA gene are 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. The majority of GISTs associated with a mutation in the PDGFRA gene occur in the stomach. In most cases, the genetic changes 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, PDGFRA gene mutations that increase the risk of developing GISTs are inherited from a parent, which can lead to familial GISTs. PDGFRA gene mutations associated with GISTs create a protein that no longer requires binding of the platelet-derived growth factor protein to be activated. As a result, the PDGFRA protein and the signaling pathways are constitutively activated, which increases cell proliferation and survival, leading to tumor formation. PDGFRA-associated chronic eosinophilic leukemia Genetic abnormalities that involve the PDGFRA gene cause a type of blood cell cancer called PDGFRA-associated chronic eosinophilic leukemia. This condition is characterized by an increased number of eosinophils, a type of white blood cell involved in allergic reactions. These genetic abnormalities are somatic mutations, which are mutations acquired during a person's lifetime that are present only in certain cells. The most common of these genetic abnormalities is a deletion of genetic material from chromosome 4 that brings together parts of two genes, FIP1L1 and PDGFRA, creating the FIP1L1-PDGFRA fusion gene. Occasionally, genes other than FIP1L1 are fused with the PDGFRA gene. Mutations that change single DNA building blocks in the PDGFRA gene (point mutations) can also cause this condition, although these mutations are seen very rarely. The protein produced from the FIP1L1-PDGFRA fusion gene (as well as other PDGFRA fusion genes) has the function of the PDGFRA protein. However, unlike the normal PDGFRA protein, the fusion protein does not require binding of the platelet-derived growth factor protein to be activated. Similarly, point mutations in the PDGFRA gene can result in a PDGFRA protein that is activated without ligand binding. As a result, the signaling pathways are constantly turned on (constitutively activated), which increases the proliferation and survival of cells. When the FIP1L1-PDGFRA fusion gene mutation or point mutations in the PDGFRA gene occur in early blood cells, the growth of eosinophils (and occasionally other blood cells) is poorly controlled, leading to PDGFRA-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change. other disorders PDGFRA gene mutations that lead to a constitutively active PDGFRA protein are also associated with inflammatory fibroid polyps, which are small, noncancerous (benign) tumors that form in the gastrointestinal tract. These tumors are made up of fibrous tissue and usually contain cells known to cause inflammation (inflammatory cells). As in GISTs, the constitutively active PDGFRA protein leads to the overgrowth of cells and formation of tumors.

     The PDGFRA gene provides instructions for making a protein called platelet-derived growth factor receptor alpha (PDGFRA), which is part of a family of proteins called receptor tyrosine kinases (RTKs). Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The PDGFRA protein is found in the cell membrane of certain cell types where a specific protein, called platelet-derived growth factor, attaches (binds) to it. This binding turns on (activates) the PDGFRA protein, which then activates other proteins inside the cell by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions (a process called phosphorylation). This process leads to the activation of a series of proteins in multiple signaling pathways. The signaling pathways stimulated by the PDGFRA protein control many important cellular processes such as cell growth and division (proliferation) and cell survival. PDGFRA protein signaling is important for the development of many types of cells throughout the body.

The following transcription factors affect gene expression:

• C/EBPbeta
• HNF-4alpha1
• HNF-4alpha2
• c-Rel
• NF-1
• c-Myb

Tissue specificity:

Detected in platelets (at protein level). Widely expressed. Detected in brain, fibroblasts, smooth muscle, heart, and embryo. Expressed in primary and metastatic colon tumors and in normal colon tissue.

Enzyme Regulation:

Present in an inactive conformation in the absence of bound ligand. Binding of PDGFA and/or PDGFB leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by imatinib, nilotinib and sorafenib.

Molecular Function:

• Transmembrane Receptor Protein Tyrosine Kinase Activity
• Platelet-Derived Growth Factor Alpha-Receptor Activity
• Vascular Endothelial Growth Factor-Activated Receptor Activity
• Ras Guanyl-Nucleotide Exchange Factor Activity
• Platelet-Derived Growth Factor Receptor Binding
• Atp Binding
• Vascular Endothelial Growth Factor Binding
• Protein Homodimerization Activity
• Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Activity
• Platelet-Derived Growth Factor Binding

Biological Processes:

• Mapk Cascade
• Luteinization
• Cell Activation
• Positive Regulation Of Cytosolic Calcium Ion Concentration
• Positive Regulation Of Cell Proliferation
• Negative Regulation Of Platelet Activation
• Positive Regulation Of Phospholipase C Activity
• Regulation Of Phosphatidylinositol 3-Kinase Signaling
• Positive Regulation Of Phosphatidylinositol 3-Kinase Signaling
• Viral Process
• Peptidyl-Tyrosine Phosphorylation
• Positive Regulation Of Cell Migration
• Cellular Response To Reactive Oxygen Species
• Platelet-Derived Growth Factor Receptor-Alpha Signaling Pathway
• Positive Regulation Of Cell Proliferation By Vegf-Activated Platelet Derived Growth Factor Receptor Signaling Pathway
• Wound Healing
• Positive Regulation Of Phosphatidylinositol 3-Kinase Activity
• Positive Regulation Of Dna Replication
• Protein Autophosphorylation
• Platelet-Derived Growth Factor Receptor Signaling Pathway
• Phosphatidylinositol-Mediated Signaling
• Positive Regulation Of Fibroblast Proliferation
• Embryonic Digestive Tract Morphogenesis
• Embryonic Cranial Skeleton Morphogenesis
• Embryonic Skeletal System Morphogenesis
• Regulation Of Chemotaxis
• Cardiac Myofibril Assembly
• Cell Chemotaxis
• Retina Vasculature Development In Camera-Type Eye
• Positive Regulation Of Erk1 And Erk2 Cascade
• Platelet Aggregation
• Metanephric Glomerular Capillary Formation
• Regulation Of Actin Cytoskeleton Reorganization
• Regulation Of Mesenchymal Stem Cell Differentiation

Drug Bank:

• Becaplermin
• Imatinib
• Ponatinib
• Sunitinib
• Pazopanib
• Regorafenib