Genomes and Genes
platelet derived growth factor alpha receptor
Summary: A PDGF receptor that binds specifically to both PDGF-A chains and PDGF-B chains. It contains a protein-tyrosine kinase activity that is involved in SIGNAL TRANSDUCTION.
- Lasota J, Miettinen M. Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours. Histopathology. 2008;53:245-66 pubmed publisher..GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors. ..
- Lee H, Kim M, Lee H, Lee B, Kim W. Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C theta immunostaining. J Clin Pathol. 2008;61:722-9 pubmed publisher..Although PKC is a sensitive diagnostic marker for GIST, its usefulness is limited because of low sensitivity and low specificity in KIT-negative GISTs. ..
- Steigen S, Eide T, Wasag B, Lasota J, Miettinen M. Mutations in gastrointestinal stromal tumors--a population-based study from Northern Norway. APMIS. 2007;115:289-98 pubmed..KIT and PDGFRA wild type was found in 15% of cases. Analysis of KIT and PDGFRA mutations is of significance for treatment with tyrosine kinase inhibitors, and may also have value when assessing the biological potential of GIST. ..
- Lei H, Hovland P, Velez G, Haran A, Gilbertson D, Hirose T, et al. A potential role for PDGF-C in experimental and clinical proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2007;48:2335-42 pubmed..Finally, these findings implicate one of the new PDGF family members as an important contributor to experimental and clinical PVR. ..
- Daum O, Grossmann P, Vanecek T, Sima R, Mukensnabl P, Michal M. Diagnostic morphological features of PDGFRA-mutated gastrointestinal stromal tumors: molecular genetic and histologic analysis of 60 cases of gastric gastrointestinal stromal tumors. Ann Diagn Pathol. 2007;11:27-33 pubmed..Finally, tumor-infiltrating lymphocytes and myxoid stroma do not seem to be valuable histologic signs. ..
- Heinrich M, Owzar K, Corless C, Hollis D, Borden E, Fletcher C, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncolo. J Clin Oncol. 2008;26:5360-7 pubmed publisher..We confirmed the favorable impact of KIT exon 11 genotype when compared with KIT exon 9 and wild-type genotype for patients with advanced GIST who are treated with imatinib. ..
- Darabi R, Gehlbach K, Bachoo R, Kamath S, Osawa M, Kamm K, et al. Functional skeletal muscle regeneration from differentiating embryonic stem cells. Nat Med. 2008;14:134-43 pubmed publisher..These data demonstrate the therapeutic potential of ES cells in muscular dystrophy...
- Lasota J, Miettinen M. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Semin Diagn Pathol. 2006;23:91-102 pubmed..Mutation genotyping is a tool in GIST diagnosis and in assessment of sensitivity to kinase inhibitors. This is a US government work. There are no restrictions on its use. ..
- Wardelmann E, Buttner R, Merkelbach Bruse S, Schildhaus H. Mutation analysis of gastrointestinal stromal tumors: increasing significance for risk assessment and effective targeted therapy. Virchows Arch. 2007;451:743-9 pubmed..Taken together, the molecular characterization of GISTs turns out to play a central role before and during the treatment with tyrosine kinase inhibitors, which have improved the treatment of GIST patients dramatically. ..
- Gomes A, Gouveia A, Capelinha A, de la Cruz D, Silva P, Reis R, et al. Molecular alterations of KIT and PDGFRA in GISTs: evaluation of a Portuguese series. J Clin Pathol. 2008;61:203-8 pubmed..The great majority of mutations were located in KIT exon 11, statistically associated with worse prognosis and indicative of favourable response to imatinib-based therapy in this Portuguese series of GISTs. ..
- Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-203 pubmed..By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers. ..
- Yang J, Du X, Lazar A, Pollock R, Hunt K, Chen K, et al. Genetic aberrations of gastrointestinal stromal tumors. Cancer. 2008;113:1532-43 pubmed publisher..A new paradigm of classification, integrating the standard clinical and pathological criteria with molecular aberrations, may permit personalized prognosis and treatment. ..
- Dewaele B, Wasag B, Cools J, Sciot R, Prenen H, Vandenberghe P, et al. Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation. Clin Cancer Res. 2008;14:5749-58 pubmed publisher..Treatment with dasatinib or the heat shock protein 90 inhibitor IPI-504 may provide a therapeutic alternative for GIST patients whose tumors carry the imatinib-resistant PDGFRA(D842V) mutant isoform. ..
- Braconi C, Bracci R, Bearzi I, Bianchi F, Costagliola A, Catalani R, et al. KIT and PDGFRalpha mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study. Ann Oncol. 2008;19:706-10 pubmed publisher..Point mutations and duplications in KIT exon 11 are associated with a better clinical trend in DFS. PDGFRalpha-mutated GISTs are preferentially localized in the stomach and seem to have a favorable clinical behavior. ..
- Ball S, Shuttleworth C, Kielty C. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol. 2007;177:489-500 pubmed..This mechanism was also shown to mediate human dermal fibroblast (HDF) migration. VEGF-A/PDGFR signaling has the potential to regulate vascular cell recruitment and proliferation during tissue regeneration and disease. ..
- Zhang J, Cao R, Zhang Y, Jia T, Cao Y, Wahlberg E. Differential roles of PDGFR-alpha and PDGFR-beta in angiogenesis and vessel stability. FASEB J. 2009;23:153-63 pubmed publisher..A combination of PDGF-AB and FGF-2 would be optimal proangiogenic agents for the treatment of ischemic diseases. ..
- Vrekoussis T, Stathopoulos E, Kafousi M, Navrozoglou I, Zoras O. Expression of endothelial PDGF receptors alpha and beta in breast cancer: up-regulation of endothelial PDGF receptor beta. Oncol Rep. 2007;17:1115-9 pubmed..05). No statistical difference was revealed by studying PDGFRalpha expression. In conclusion, our findings support the thesis of possible anti-PDGFRbeta anti-angiogenic therapy, in cases of endothelial PDGFRbeta-expressing breast cancer. ..
- Christensen S, Pedersen L, Schneider L, Satir P. Sensory cilia and integration of signal transduction in human health and disease. Traffic. 2007;8:97-109 pubmed..Finally, we discuss the functions of these cilia-associated signal transduction pathways and their role in human health and development. ..
- Do I, Araujo E, Kalil R, Bacchini P, Bertoni F, Unni K, et al. Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas. Pathol Res Pract. 2007;203:127-34 pubmed..These findings imply other mechanisms for KIT activity and leave open the question of whether imatinib would be efficacious in the treatment of Ewing sarcoma. ..
- Puputti M, Tynninen O, Sihto H, Blom T, Mäenpää H, Isola J, et al. Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res. 2006;4:927-34 pubmed..It is currently not known whether specific tyrosine kinase inhibitors are effective in the treatment of such gliomas. ..
- Wozniak A, Sciot R, Guillou L, Pauwels P, Wasag B, Stul M, et al. Array CGH analysis in primary gastrointestinal stromal tumors: cytogenetic profile correlates with anatomic site and tumor aggressiveness, irrespective of mutational status. Genes Chromosomes Cancer. 2007;46:261-76 pubmed..32-1p35.2, 1p34.1, and 1p22.1-1p21.3), 13q (13q14.11-q14.2 and 13q32.3-q33.1), and 15q23 were delineated, which point to chromosomal regions that may harbor genes relevant to the development of these neoplasms. ..
- Tamborini E, Miselli F, Negri T, Lagonigro M, Staurengo S, Dagrada G, et al. Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas. Clin Cancer Res. 2006;12:6920-8 pubmed..No role seems to be played by gene amplification. In the light of our findings, the clinical benefit observed in chordoma patients treated with imatinib seems to be attributable to the switching off of all three receptors. ..
- Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23:70-83 pubmed..Immunohistochemical demonstration of KIT, CD34, or protein kinase theta positivity helps to properly identify these tumors. ..
- Kitamura Y. Gastrointestinal stromal tumors: past, present, and future. J Gastroenterol. 2008;43:499-508 pubmed publisher..New drugs and adjuvant regimens against such secondary progression are now being intensively explored. ..
- Stover E, Chen J, Lee B, Cools J, McDowell E, Adelsperger J, et al. The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRbeta and FIP1L1-PDGFRalpha in vitro and in vivo. Blood. 2005;106:3206-13 pubmed..In summary, AMN107 can inhibit myeloid proliferation driven by TEL-PDGFRbeta and FIP1L1-PDGFRalpha and may be a useful drug for treatment of patients with myeloproliferative disease who harbor these kinase fusions. ..
- Corless C, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23:5357-64 pubmed..However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors. ..
- Prenen H, Cools J, Mentens N, Folens C, Sciot R, Schoffski P, et al. Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res. 2006;12:2622-7 pubmed..Specific kinase inhibitors should be designed to inhibit the constitutive activating PDGFRA mutation at codon 842. ..
- Antonescu C, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182-90 pubmed..That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies. ..
- McIntyre A, Summersgill B, Grygalewicz B, Gillis A, Stoop J, van Gurp R, et al. Amplification and overexpression of the KIT gene is associated with progression in the seminoma subtype of testicular germ cell tumors of adolescents and adults. Cancer Res. 2005;65:8085-9 pubmed
- Lasota J, Stachura J, Miettinen M. GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology. Lab Invest. 2006;86:94-100 pubmed..In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease. ..
- Holtkamp N, Okuducu A, Mucha J, Afanasieva A, Hartmann C, Atallah I, et al. Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity. Carcinogenesis. 2006;27:664-71 pubmed..In summary, PDGFRA, PDGF and KIT dysregulation as well as growth inhibition of cell culture S462 by imatinib may suggest that MPNST patients benefit from treatment with imatinib. ..
- Reis R, Martins A, Ribeiro S, Basto D, Longatto Filho A, Schmitt F, et al. Molecular characterization of PDGFR-alpha/PDGF-A and c-KIT/SCF in gliosarcomas. Cell Oncol. 2005;27:319-26 pubmed..Nevertheless, the presence of a PDGFR-a/PDGFA and c-Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in the treatment of gliosarcomas. ..
- Kang H, Koh K, Yang E, You K, Kim H, Paik Y, et al. Differentially expressed proteins in gastrointestinal stromal tumors with KIT and PDGFRA mutations. Proteomics. 2006;6:1151-7 pubmed..Moreover, it may play a role in the development and progression of GIST according to activating mutation type, as these proteins have been shown to be involved in tumor metastasis, apoptosis and immune response. ..
- Andersson J, Bümming P, Meis Kindblom J, Sihto H, Nupponen N, Joensuu H, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology. 2006;130:1573-81 pubmed..KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively. KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST. ..
- Tornillo L, Terracciano L. An update on molecular genetics of gastrointestinal stromal tumours. J Clin Pathol. 2006;59:557-63 pubmed..A new paradigm of classification integrating the classic pathological criteria with the molecular changes will permit personalised prognosis and treatment. ..
- Jackson E, Garcia Verdugo J, Gil Perotin S, Roy M, Quinones Hinojosa A, Vandenberg S, et al. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron. 2006;51:187-99 pubmed..Excessive PDGF activation in the SVZ in stem cells is sufficient to induce hallmarks associated with early stages of tumor formation. ..
- Weisberg E, Wright R, Jiang J, Ray A, Moreno D, Manley P, et al. Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity. Gastroenterology. 2006;131:1734-42 pubmed..The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST. ..
- Cho S, Kitadai Y, Yoshida S, Tanaka S, Yoshihara M, Yoshida K, et al. Deletion of the KIT gene is associated with liver metastasis and poor prognosis in patients with gastrointestinal stromal tumor in the stomach. Int J Oncol. 2006;28:1361-7 pubmed..Our data indicate that KIT mutations, especially deletions in exon 11, are markers of poor prognosis for gastric GISTs. ..
- Joensuu H, Puputti M, Sihto H, Tynninen O, Nupponen N. Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J Pathol. 2005;207:224-31 pubmed..We conclude that KIT, PDGFRA and VEGFR2 are commonly amplified in primary glioblastoma and that they may also be amplified in secondary glioblastoma. Amplified kinases may be potential targets for tyrosine kinase inhibitor therapy. ..
- Martin J, Poveda A, Llombart Bosch A, Ramos R, Lopez Guerrero J, García del Muro J, et al. Deletions affecting codons 557-558 of the c-KIT gene indicate a poor prognosis in patients with completely resected gastrointestinal stromal tumors: a study by the Spanish Group for Sarcoma Research (GEIS). J Clin Oncol. 2005;23:6190-8 pubmed..This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients. ..
- Carvalho I, Milanezi F, Martins A, Reis R, Schmitt F. Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression. Breast Cancer Res. 2005;7:R788-95 pubmed
- Schneider L, Clement C, Teilmann S, Pazour G, Hoffmann E, Satir P, et al. PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts. Curr Biol. 2005;15:1861-6 pubmed..We propose that ciliary PDGFRalphaalpha signaling is linked to tissue homeostasis and to mitogenic signaling pathways. ..
- Ball S, Shuttleworth C, Kielty C. Platelet-derived growth factor receptor-alpha is a key determinant of smooth muscle alpha-actin filaments in bone marrow-derived mesenchymal stem cells. Int J Biochem Cell Biol. 2007;39:379-91 pubmed..This study thus provides new insights into the distinct roles of platelet-derived growth factor receptor-alpha and -beta signaling in regulating the adult mesenchymal stem cell contractile cytoskeleton. ..
- Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest. 2006;116:1561-70 pubmed..Thus, autocrine PDGFR signaling plays an essential role during cancer progression, suggesting a novel application of STI571 to therapeutically interfere with metastasis. ..
- Anderberg C, Li H, Fredriksson L, Andrae J, Betsholtz C, Li X, et al. Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res. 2009;69:369-78 pubmed publisher..In conclusion, we establish paracrine signaling by PDGF-CC as a potential drug target to reduce stromal support in malignant melanoma. ..
- Terada T. Gastrointestinal stromal tumor of the uterus: a case report with genetic analyses of c-kit and PDGFRA genes. Int J Gynecol Pathol. 2009;28:29-34 pubmed publisher..Other exons showed no abnormalities. This case shows that gastrointestinal stromal tumor may occur in the uterus. ..
- Thao L, Vu H, Yasuda K, Taniguchi S, Yagasaki F, Taguchi T, et al. Cas-L was overexpressed in imatinib-resistant gastrointestinal stromal tumor cells. Cancer Biol Ther. 2009;8:683-8 pubmed..We report for the first time that the mechanism of imatinib-resistant GISTs, at least in one cell line, involves KIT/Cas-L/SRC signaling. Cas-L depletion sensitized the resistant GIST-T1 IR cells to imatinib. ..
- Klion A, Robyn J, Maric I, Fu W, Schmid L, Lemery S, et al. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood. 2007;110:3552-6 pubmed..This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304. ..
- Kim J, Boo Y, Jung C, Park S, Kim S, Mok Y, et al. Multiple malignant extragastrointestinal stromal tumors of the greater omentum and results of immunohistochemistry and mutation analysis: a case report. World J Gastroenterol. 2007;13:3392-5 pubmed..From above findings, we proposed that there may be several mutational pathways to malignant EGIST, so further investigations could be needed to approach this unfavorable disease entity. ..
- Bian Y, Huang S, Yang L, Ma X, Xie J, Zhang H. Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas. World J Gastroenterol. 2007;13:1659-65 pubmed..Expression of Gli3 could not be detected in colorectal adenocarcinomas. These data suggest that Shh-Ptch1-Gli1 signaling pathway may play a role in the progression of colorectal tumor. ..
- Baruchel S, Sharp J, Bartels U, Hukin J, Odame I, Portwine C, et al. A Canadian paediatric brain tumour consortium (CPBTC) phase II molecularly targeted study of imatinib in recurrent and refractory paediatric central nervous system tumours. Eur J Cancer. 2009;45:2352-9 pubmed publisher..Imatinib at 440 mg/m(2)/day is relatively safe in children with recurrent CNS tumours, but induced no objective responses. Demonstration of SD in previously progressing patients (KIT-expressing) suggests cytostatic activity of imatinib. ..
- McCarthy N, Jones H, Marks N, Shiner R, Ind P, Al Hassi H, et al. Inhaled allergen-driven CD1c up-regulation and enhanced antigen uptake by activated human respiratory-tract dendritic cells in atopic asthma. Clin Exp Allergy. 2007;37:72-82 pubmed..CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies. ..