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PDGFRA  -  platelet-derived growth factor receptor,...

Homo sapiens

 
 
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Disease relevance of PDGFRA

 

Psychiatry related information on PDGFRA

  • Using DNA of a patient with piebaldism, mental retardation, and multiple congenital anomalies associated with a 46,XY,del(4) (q12q21.1) karyotype, we carried out quantitative Southern blot hybridization analyses of the KIT gene and the adjacent PDGFRA (platelet-derived growth factor receptor alpha subunit) genes [5].
 

High impact information on PDGFRA

 

Chemical compound and disease context of PDGFRA

 

Biological context of PDGFRA

  • A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1) [14].
  • Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity [14].
  • Mutational analysis of exons 9, 11, 13, and 17 of KIT, and exons 12 and 18 of PDGFRA was performed in all cases by denaturing high-pressure liquid chromatography (DHPLC) pre-screening, followed by direct sequencing [15].
  • However, although the incidence of MPD involving translocations of PDGFRB has been well established, to our knowledge there are only two previous reports describing a BCR-PDGFRA fusion gene, in 3 patients diagnosed with atypical CML [16].
  • Here, we report the molecular and cytogenetic characterization of a patient with BCR-PDGFRA-positive MPD who had a complete hematologic response after treatment with imatinib mesylate [16].
 

Anatomical context of PDGFRA

 

Associations of PDGFRA with chemical compounds

  • Treatment with low-dose imatinib (100 mg/d) produced complete and durable responses in all 8 FIP1L1-PDGFRA(+) cases treated [1].
  • Three tumours harboured PDGFRA exon 18 activating mutations; two were Asp --> Val(842) missense substitutions and one was a DIM842-844 amino acid deletion [15].
  • These rare neoplasms are remarkably sensitive to the KIT and PDGFRA kinase inhibitors imatinib (also known as Gleevec) and sunitinib (Sutent), which have recently been approved as the standard therapeutic courses for patients with inoperable GIST [8].
  • We detected a germline PDGFRA missense mutation, 2675G > T, resulting in a tyrosine substitution for the highly conserved aspartic acid at codon 846 [18].
  • Alternately, the mutant kinase proteins can be targeted using HSP90 inhibitors, which result in degradation of activated KIT and/or PDGFRA, or using KIT transcriptional repressors, such as flavopiridol [8].
  • This study is the largest reported to date on patients with advanced PDGFRA-mutant GISTs treated with imatinib [19].
 

Physical interactions of PDGFRA

  • All three matrices have been shown to purify a 90-kDa protein that is recognized by mAbs specific for the PDGF-R alpha extracellular domain. sPDGF-R alpha is capable of binding PDGF ligand in solution and can compete with cell-associated PDGF receptors for ligand binding [20].
 

Regulatory relationships of PDGFRA

  • This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature [21].
  • In addition, PDGF-BB, in the presence of anti-PDGF-R beta, bound only to PDGF-R alpha and caused suppression of SMC migration induced by fibronectin [22].
  • The TGF-beta 1-induced down-regulation of the PDGF-R alpha gene was rapid (maximal suppression by 2 h post-treatment) and preceded the decrease in cell-surface alpha-receptor (maximal reduction by 6 h post-treatment) [23].
  • AF tumors expressed minimal to null levels of KIT and PDGFRA but expressed levels of PDGFRB that are comparable with normal fibroblasts [24].
  • Intestinal Neurofibromatosis Is a Subtype of Familial GIST and Results From a Dominant Activating Mutation in PDGFRA [25].
 

Other interactions of PDGFRA

  • This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management [14].
  • No mutations were detected with denaturing high-performance liquid chromatography in KIT exons 9, 11, 13 or 17, PDGFRA exons 12 and 18, or EGFR exons 18, 19 or 21 [4].
  • 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 [10].
  • Point mutations of c-kit gene or PDGFRA gene were identified only in three (8%) and two (6%) tumors, respectively [26].
  • This article describes the results of comprehensive molecular/biochemical analyses of the three receptors targeted by the drug (PDGFRB, PDGFRA, and KIT) in a series of 31 chordoma patients [27].
 

Analytical, diagnostic and therapeutic context of PDGFRA

References

  1. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Pardanani, A., Brockman, S.R., Paternoster, S.F., Flynn, H.C., Ketterling, R.P., Lasho, T.L., Ho, C.L., Li, C.Y., Dewald, G.W., Tefferi, A. Blood (2004) [Pubmed]
  2. The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Cools, J., Quentmeier, H., Huntly, B.J., Marynen, P., Griffin, J.D., Drexler, H.G., Gilliland, D.G. Blood (2004) [Pubmed]
  3. Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Pardanani, A., Tefferi, A. Blood (2004) [Pubmed]
  4. Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. Joensuu, H., Puputti, M., Sihto, H., Tynninen, O., Nupponen, N.N. J. Pathol. (2005) [Pubmed]
  5. Deletion of the KIT and PDGFRA genes in a patient with piebaldism. Spritz, R.A., Droetto, S., Fukushima, Y. Am. J. Med. Genet. (1992) [Pubmed]
  6. Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects. Joosten, P.H., Toepoel, M., Mariman, E.C., Van Zoelen, E.J. Nat. Genet. (2001) [Pubmed]
  7. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. MacDonald, T.J., Brown, K.M., LaFleur, B., Peterson, K., Lawlor, C., Chen, Y., Packer, R.J., Cogen, P., Stephan, D.A. Nat. Genet. (2001) [Pubmed]
  8. KIT Mutations in GIST. Fletcher, J.A., Rubin, B.P. Curr. Opin. Genet. Dev. (2007) [Pubmed]
  9. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Pardanani, A., Ketterling, R.P., Brockman, S.R., Flynn, H.C., Paternoster, S.F., Shearer, B.M., Reeder, T.L., Li, C.Y., Cross, N.C., Cools, J., Gilliland, D.G., Dewald, G.W., Tefferi, A. Blood (2003) [Pubmed]
  10. Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity. Holtkamp, N., Okuducu, A.F., Mucha, J., Afanasieva, A., Hartmann, C., Atallah, I., Estevez-Schwarz, L., Mawrin, C., Friedrich, R.E., Mautner, V.F., von Deimling, A. Carcinogenesis (2006) [Pubmed]
  11. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. Cools, J., DeAngelo, D.J., Gotlib, J., Stover, E.H., Legare, R.D., Cortes, J., Kutok, J., Clark, J., Galinsky, I., Griffin, J.D., Cross, N.C., Tefferi, A., Malone, J., Alam, R., Schrier, S.L., Schmid, J., Rose, M., Vandenberghe, P., Verhoef, G., Boogaerts, M., Wlodarska, I., Kantarjian, H., Marynen, P., Coutre, S.E., Stone, R., Gilliland, D.G. N. Engl. J. Med. (2003) [Pubmed]
  12. Multilineage involvement of the fusion gene in patients with FIP1L1/PDGFRA-positive hypereosinophilic syndrome. Robyn, J., Lemery, S., McCoy, J.P., Kubofcik, J., Kim, Y.J., Pack, S., Nutman, T.B., Dunbar, C., Klion, A.D. Br. J. Haematol. (2006) [Pubmed]
  13. A regulating element essential for PDGFRA transcription is recognized by neural tube defect-associated PRX homeobox transcription factors. Joosten, P.H., Toepoel, M., van Oosterhout, D., Afink, G.B., van Zoelen, E.J. Biochim. Biophys. Acta (2002) [Pubmed]
  14. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Gotlib, J., Cools, J., Malone, J.M., Schrier, S.L., Gilliland, D.G., Coutré, S.E. Blood (2004) [Pubmed]
  15. Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. Debiec-Rychter, M., Wasag, B., Stul, M., De Wever, I., Van Oosterom, A., Hagemeijer, A., Sciot, R. J. Pathol. (2004) [Pubmed]
  16. Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia. Safley, A.M., Sebastian, S., Collins, T.S., Tirado, C.A., Stenzel, T.T., Gong, J.Z., Goodman, B.K. Genes Chromosomes Cancer (2004) [Pubmed]
  17. The human PDGF receptor alpha-subunit gene maps to chromosome 4 in close proximity to c-kit. Gronwald, R.G., Adler, D.A., Kelly, J.D., Disteche, C.M., Bowen-Pope, D.F. Hum. Genet. (1990) [Pubmed]
  18. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Chompret, A., Kannengiesser, C., Barrois, M., Terrier, P., Dahan, P., Tursz, T., Lenoir, G.M., Bressac-De Paillerets, B. Gastroenterology (2004) [Pubmed]
  19. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Cassier, P.A., Fumagalli, E., Rutkowski, P., Schöffski, P., Van Glabbeke, M., Debiec-Rychter, M., Emile, J.F., Duffaud, F., Martin-Broto, J., Landi, B., Adenis, A., Bertucci, F., Bompas, E., Bouché, O., Leyvraz, S., Judson, I., Verweij, J., Casali, P., Blay, J.Y., Hohenberger, P. Clin. Cancer Res. (2012) [Pubmed]
  20. Identification of a soluble receptor for platelet-derived growth factor in cell-conditioned medium and human plasma. Tiesman, J., Hart, C.E. J. Biol. Chem. (1993) [Pubmed]
  21. Epithelioid gastrointestinal stromal tumor with PDGFRA activating mutation and immunoreactivity. Yi, E.S., Strong, C.R., Piao, Z., Perucho, M., Weidner, N. Appl. Immunohistochem. Mol. Morphol. (2005) [Pubmed]
  22. Different functions of the platelet-derived growth factor-alpha and -beta receptors for the migration and proliferation of cultured baboon smooth muscle cells. Koyama, N., Hart, C.E., Clowes, A.W. Circ. Res. (1994) [Pubmed]
  23. Transforming growth factor beta 1 downregulates the platelet-derived growth factor alpha-receptor subtype on human lung fibroblasts in vitro. Bonner, J.C., Badgett, A., Lindroos, P.M., Osornio-Vargas, A.R. Am. J. Respir. Cell Mol. Biol. (1995) [Pubmed]
  24. Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor). Heinrich, M.C., McArthur, G.A., Demetri, G.D., Joensuu, H., Bono, P., Herrmann, R., Hirte, H., Cresta, S., Koslin, D.B., Corless, C.L., Dirnhofer, S., van Oosterom, A.T., Nikolova, Z., Dimitrijevic, S., Fletcher, J.A. J. Clin. Oncol. (2006) [Pubmed]
  25. Intestinal Neurofibromatosis Is a Subtype of Familial GIST and Results From a Dominant Activating Mutation in PDGFRA. de Raedt, T., Cools, J., Debiec-Rychter, M., Brems, H., Mentens, N., Sciot, R., Himpens, J., de Wever, I., Sch??ffski, P., Marynen, P., Legius, E. Gastroenterology (2006) [Pubmed]
  26. Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease). Takazawa, Y., Sakurai, S., Sakuma, Y., Ikeda, T., Yamaguchi, J., Hashizume, Y., Yokoyama, S., Motegi, A., Fukayama, M. Am. J. Surg. Pathol. (2005) [Pubmed]
  27. Molecular and Biochemical Analyses of Platelet-Derived Growth Factor Receptor (PDGFR) B, PDGFRA, and KIT Receptors in Chordomas. Tamborini, E., Miselli, F., Negri, T., Lagonigro, M.S., Staurengo, S., Dagrada, G.P., Stacchiotti, S., Pastore, E., Gronchi, A., Perrone, F., Carbone, A., Pierotti, M.A., Casali, P.G., Pilotti, S. Clin. Cancer Res. (2006) [Pubmed]
  28. Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors. Shinomura, Y., Kinoshita, K., Tsutsui, S., Hirota, S. J. Gastroenterol. (2005) [Pubmed]
  29. The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Baxter, E.J., Hochhaus, A., Bolufer, P., Reiter, A., Fernandez, J.M., Senent, L., Cervera, J., Moscardo, F., Sanz, M.A., Cross, N.C. Hum. Mol. Genet. (2002) [Pubmed]
  30. Correlation of KIT and platelet-derived growth factor receptor alpha mutations with gene activation and expression profiles in gastrointestinal stromal tumors. Kang, H.J., Nam, S.W., Kim, H., Rhee, H., Kim, N.G., Kim, H., Hyung, W.J., Noh, S.H., Kim, J.H., Yun, C.O., Liu, E.T., Kim, H. Oncogene (2005) [Pubmed]
 
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