Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2000 Nov;37(11):817–827. doi: 10.1136/jmg.37.11.817

Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis

J Hansford 1, L Mulligan 1
PMCID: PMC1734482  PMID: 11073534

Abstract

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome characterised by medullary thyroid carcinoma (MTC), with or without phaeochromocytoma and hyperparathyroidism. MEN 2 is unusual among cancer syndromes as it is caused by activation of a cellular oncogene, RET. Germline mutations in the gene encoding the RET receptor tyrosine kinase are found in the vast majority of MEN 2 patients and somatic RET mutations are found in a subset of sporadic MTC. Further, there are strong associations of RET mutation genotype and disease phenotype in MEN 2 which have led to predictions of tissue specific requirements and sensitivities to RET activity. Our ability to identify genetically, with high accuracy, subjects with MEN 2 has revolutionised our ability to diagnose, predict, and manage this disease. In the past few years, studies of RET and its normal ligand and downstream interactions and the signalling pathways it activates have clarified our understanding of the roles played by RET in normal cell survival, proliferation, and differentiation, as well as in disease. Here, we review the current knowledge of the normal functions of RET and the effects of mutations of this gene in tumorigenesis and in normal development.


Keywords: multiple endocrine neoplasia type 2; RET; receptor tyrosine kinase

Full Text

The Full Text of this article is available as a PDF (198.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alberti L., Borrello M. G., Ghizzoni S., Torriti F., Rizzetti M. G., Pierotti M. A. Grb2 binding to the different isoforms of Ret tyrosine kinase. Oncogene. 1998 Sep 3;17(9):1079–1087. doi: 10.1038/sj.onc.1202046. [DOI] [PubMed] [Google Scholar]
  2. Angrist M., Bolk S., Halushka M., Lapchak P. A., Chakravarti A. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet. 1996 Nov;14(3):341–344. doi: 10.1038/ng1196-341. [DOI] [PubMed] [Google Scholar]
  3. Angrist M., Jing S., Bolk S., Bentley K., Nallasamy S., Halushka M., Fox G. M., Chakravarti A. Human GFRA1: cloning, mapping, genomic structure, and evaluation as a candidate gene for Hirschsprung disease susceptibility. Genomics. 1998 Mar 15;48(3):354–362. doi: 10.1006/geno.1997.5191. [DOI] [PubMed] [Google Scholar]
  4. Arighi E., Alberti L., Torriti F., Ghizzoni S., Rizzetti M. G., Pelicci G., Pasini B., Bongarzone I., Piutti C., Pierotti M. A. Identification of Shc docking site on Ret tyrosine kinase. Oncogene. 1997 Feb 20;14(7):773–782. doi: 10.1038/sj.onc.1200896. [DOI] [PubMed] [Google Scholar]
  5. Asai N., Iwashita T., Matsuyama M., Takahashi M. Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol. 1995 Mar;15(3):1613–1619. doi: 10.1128/mcb.15.3.1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Asai N., Murakami H., Iwashita T., Takahashi M. A mutation at tyrosine 1062 in MEN2A-Ret and MEN2B-Ret impairs their transforming activity and association with shc adaptor proteins. J Biol Chem. 1996 Jul 26;271(30):17644–17649. doi: 10.1074/jbc.271.30.17644. [DOI] [PubMed] [Google Scholar]
  7. Attié T., Pelet A., Edery P., Eng C., Mulligan L. M., Amiel J., Boutrand L., Beldjord C., Nihoul-Fékété C., Munnich A. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995 Aug;4(8):1381–1386. doi: 10.1093/hmg/4.8.1381. [DOI] [PubMed] [Google Scholar]
  8. Auricchio A., Griseri P., Carpentieri M. L., Betsos N., Staiano A., Tozzi A., Priolo M., Thompson H., Bocciardi R., Romeo G. Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. Am J Hum Genet. 1999 Apr;64(4):1216–1221. doi: 10.1086/302329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Avantaggiato V., Dathan N. A., Grieco M., Fabien N., Lazzaro D., Fusco A., Simeone A., Santoro M. Developmental expression of the RET protooncogene. Cell Growth Differ. 1994 Mar;5(3):305–311. [PubMed] [Google Scholar]
  10. Baloh R. H., Enomoto H., Johnson E. M., Jr, Milbrandt J. The GDNF family ligands and receptors - implications for neural development. Curr Opin Neurobiol. 2000 Feb;10(1):103–110. doi: 10.1016/s0959-4388(99)00048-3. [DOI] [PubMed] [Google Scholar]
  11. Berndt I., Reuter M., Saller B., Frank-Raue K., Groth P., Grussendorf M., Raue F., Ritter M. M., Höppner W. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998 Mar;83(3):770–774. doi: 10.1210/jcem.83.3.4619. [DOI] [PubMed] [Google Scholar]
  12. Bilang-Bleuel A., Revah F., Colin P., Locquet I., Robert J. J., Mallet J., Horellou P. Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8818–8823. doi: 10.1073/pnas.94.16.8818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Boccia L. M., Green J. S., Joyce C., Eng C., Taylor S. A., Mulligan L. M. Mutation of RET codon 768 is associated with the FMTC phenotype. Clin Genet. 1997 Feb;51(2):81–85. doi: 10.1111/j.1399-0004.1997.tb02424.x. [DOI] [PubMed] [Google Scholar]
  14. Bocciardi R., Mograbi B., Pasini B., Borrello M. G., Pierotti M. A., Bourget I., Fischer S., Romeo G., Rossi B. The multiple endocrine neoplasia type 2B point mutation switches the specificity of the Ret tyrosine kinase towards cellular substrates that are susceptible to interact with Crk and Nck. Oncogene. 1997 Nov 6;15(19):2257–2265. doi: 10.1038/sj.onc.1201413. [DOI] [PubMed] [Google Scholar]
  15. Bolino A., Schuffenecker I., Luo Y., Seri M., Silengo M., Tocco T., Chabrier G., Houdent C., Murat A., Schlumberger M. RET mutations in exons 13 and 14 of FMTC patients. Oncogene. 1995 Jun 15;10(12):2415–2419. [PubMed] [Google Scholar]
  16. Bolk S., Pelet A., Hofstra R. M., Angrist M., Salomon R., Croaker D., Buys C. H., Lyonnet S., Chakravarti A. A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):268–273. doi: 10.1073/pnas.97.1.268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Borrego S., Sáez M. E., Ruiz A., Gimm O., López-Alonso M., Antiñolo G., Eng C. Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression. J Med Genet. 1999 Oct;36(10):771–774. doi: 10.1136/jmg.36.10.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Borrello M. G., Alberti L., Arighi E., Bongarzone I., Battistini C., Bardelli A., Pasini B., Piutti C., Rizzetti M. G., Mondellini P. The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase Cgamma. Mol Cell Biol. 1996 May;16(5):2151–2163. doi: 10.1128/mcb.16.5.2151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Borrello M. G., Pelicci G., Arighi E., De Filippis L., Greco A., Bongarzone I., Rizzetti M., Pelicci P. G., Pierotti M. A. The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb2 adaptor proteins. Oncogene. 1994 Jun;9(6):1661–1668. [PubMed] [Google Scholar]
  20. Borrello M. G., Smith D. P., Pasini B., Bongarzone I., Greco A., Lorenzo M. J., Arighi E., Miranda C., Eng C., Alberti L. RET activation by germline MEN2A and MEN2B mutations. Oncogene. 1995 Dec 7;11(11):2419–2427. [PubMed] [Google Scholar]
  21. Borst M. J., VanCamp J. M., Peacock M. L., Decker R. A. Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease. Surgery. 1995 Apr;117(4):386–391. doi: 10.1016/s0039-6060(05)80057-1. [DOI] [PubMed] [Google Scholar]
  22. Califano D., Monaco C., de Vita G., D'Alessio A., Dathan N. A., Possenti R., Vecchio G., Fusco A., Santoro M., de Franciscis V. Activated RET/PTC oncogene elicits immediate early and delayed response genes in PC12 cells. Oncogene. 1995 Jul 6;11(1):107–112. [PubMed] [Google Scholar]
  23. Califano D., Rizzo C., D'Alessio A., Colucci-D'Amato G. L., Cali G., Bartoli P. C., Santelli G., Vecchio G., de Franciscis V. Signaling through Ras is essential for ret oncogene-induced cell differentiation in PC12 cells. J Biol Chem. 2000 Jun 23;275(25):19297–19305. doi: 10.1074/jbc.M905866199. [DOI] [PubMed] [Google Scholar]
  24. Carlomagno F., De Vita G., Berlingieri M. T., de Franciscis V., Melillo R. M., Colantuoni V., Kraus M. H., Di Fiore P. P., Fusco A., Santoro M. Molecular heterogeneity of RET loss of function in Hirschsprung's disease. EMBO J. 1996 Jun 3;15(11):2717–2725. [PMC free article] [PubMed] [Google Scholar]
  25. Carlomagno F., Salvatore G., Cirafici A. M., De Vita G., Melillo R. M., de Franciscis V., Billaud M., Fusco A., Santoro M. The different RET-activating capability of mutations of cysteine 620 or cysteine 634 correlates with the multiple endocrine neoplasia type 2 disease phenotype. Cancer Res. 1997 Feb 1;57(3):391–395. [PubMed] [Google Scholar]
  26. Carlson K. M., Dou S., Chi D., Scavarda N., Toshima K., Jackson C. E., Wells S. A., Jr, Goodfellow P. J., Donis-Keller H. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1579–1583. doi: 10.1073/pnas.91.4.1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Carney J. A., Go V. L., Sizemore G. W., Hayles A. B. Alimentary-tract ganglioneuromatosis. A major component of the syndrome of multiple endocrine neoplasia, type 2b. N Engl J Med. 1976 Dec 2;295(23):1287–1291. doi: 10.1056/NEJM197612022952304. [DOI] [PubMed] [Google Scholar]
  28. Chappuis-Flament S., Pasini A., De Vita G., Ségouffin-Cariou C., Fusco A., Attié T., Lenoir G. M., Santoro M., Billaud M. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines. Oncogene. 1998 Dec 3;17(22):2851–2861. doi: 10.1038/sj.onc.1202202. [DOI] [PubMed] [Google Scholar]
  29. Colucci-D'Amato G. L., D'Alessio A., Califano D., Cali G., Rizzo C., Nitsch L., Santelli G., de Franciscis V. Abrogation of nerve growth factor-induced terminal differentiation by ret oncogene involves perturbation of nuclear translocation of ERK. J Biol Chem. 2000 Jun 23;275(25):19306–19314. doi: 10.1074/jbc.275.25.19306. [DOI] [PubMed] [Google Scholar]
  30. Dang G. T., Cote G. J., Schultz P. N., Khorana S., Decker R. A., Gagel R. F. A codon 891 exon 15 RET proto-oncogene mutation in familial medullary thyroid carcinoma: a detection strategy. Mol Cell Probes. 1999 Feb;13(1):77–79. doi: 10.1006/mcpr.1998.0220. [DOI] [PubMed] [Google Scholar]
  31. Donis-Keller H., Dou S., Chi D., Carlson K. M., Toshima K., Lairmore T. C., Howe J. R., Moley J. F., Goodfellow P., Wells S. A., Jr Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851–856. doi: 10.1093/hmg/2.7.851. [DOI] [PubMed] [Google Scholar]
  32. Doray B., Salomon R., Amiel J., Pelet A., Touraine R., Billaud M., Attié T., Bachy B., Munnich A., Lyonnet S. Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet. 1998 Sep;7(9):1449–1452. doi: 10.1093/hmg/7.9.1449. [DOI] [PubMed] [Google Scholar]
  33. Durbec P. L., Larsson-Blomberg L. B., Schuchardt A., Costantini F., Pachnis V. Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts. Development. 1996 Jan;122(1):349–358. doi: 10.1242/dev.122.1.349. [DOI] [PubMed] [Google Scholar]
  34. Durick K., Gill G. N., Taylor S. S. Shc and Enigma are both required for mitogenic signaling by Ret/ptc2. Mol Cell Biol. 1998 Apr;18(4):2298–2308. doi: 10.1128/mcb.18.4.2298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Durick K., Yao V. J., Borrello M. G., Bongarzone I., Pierotti M. A., Taylor S. S. Tyrosines outside the kinase core and dimerization are required for the mitogenic activity of RET/ptc2. J Biol Chem. 1995 Oct 20;270(42):24642–24645. doi: 10.1074/jbc.270.42.24642. [DOI] [PubMed] [Google Scholar]
  36. Easton D. F., Ponder M. A., Cummings T., Gagel R. F., Hansen H. H., Reichlin S., Tashjian A. H., Jr, Telenius-Berg M., Ponder B. A. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Am J Hum Genet. 1989 Feb;44(2):208–215. [PMC free article] [PubMed] [Google Scholar]
  37. Eng C., Clayton D., Schuffenecker I., Lenoir G., Cote G., Gagel R. F., van Amstel H. K., Lips C. J., Nishisho I., Takai S. I. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996 Nov 20;276(19):1575–1579. [PubMed] [Google Scholar]
  38. Eng C., Mulligan L. M., Healey C. S., Houghton C., Frilling A., Raue F., Thomas G. A., Ponder B. A. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res. 1996 May 1;56(9):2167–2170. [PubMed] [Google Scholar]
  39. Eng C., Mulligan L. M. Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes, related sporadic tumours, and hirschsprung disease. Hum Mutat. 1997;9(2):97–109. doi: 10.1002/(SICI)1098-1004(1997)9:2<97::AID-HUMU1>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  40. Eng C., Mulligan L. M., Smith D. P., Healey C. S., Frilling A., Raue F., Neumann H. P., Ponder M. A., Ponder B. A. Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 1995 Jul;43(1):123–127. doi: 10.1111/j.1365-2265.1995.tb01903.x. [DOI] [PubMed] [Google Scholar]
  41. Eng C. RET proto-oncogene in the development of human cancer. J Clin Oncol. 1999 Jan;17(1):380–393. doi: 10.1200/JCO.1999.17.1.380. [DOI] [PubMed] [Google Scholar]
  42. Eng C., Smith D. P., Mulligan L. M., Healey C. S., Zvelebil M. J., Stonehouse T. J., Ponder M. A., Jackson C. E., Waterfield M. D., Ponder B. A. A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogene. 1995 Feb 2;10(3):509–513. [PubMed] [Google Scholar]
  43. Eng C., Smith D. P., Mulligan L. M., Nagai M. A., Healey C. S., Ponder M. A., Gardner E., Scheumann G. F., Jackson C. E., Tunnacliffe A. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994 Feb;3(2):237–241. doi: 10.1093/hmg/3.2.237. [DOI] [PubMed] [Google Scholar]
  44. Eng C., Thomas G. A., Neuberg D. S., Mulligan L. M., Healey C. S., Houghton C., Frilling A., Raue F., Williams E. D., Ponder B. A. Mutation of the RET proto-oncogene is correlated with RET immunostaining in subpopulations of cells in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 1998 Dec;83(12):4310–4313. doi: 10.1210/jcem.83.12.5345. [DOI] [PubMed] [Google Scholar]
  45. Farndon J. R., Leight G. S., Dilley W. G., Baylin S. B., Smallridge R. C., Harrison T. S., Wells S. A., Jr Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg. 1986 Apr;73(4):278–281. doi: 10.1002/bjs.1800730411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Fattoruso O., Quadro L., Libroia A., Verga U., Lupoli G., Cascone E., Colantuoni V. A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET proto-oncogene in two families affected by familial medullary thyroid carcinoma. Hum Mutat. 1998;Suppl 1:S167–S171. doi: 10.1002/humu.1380110156. [DOI] [PubMed] [Google Scholar]
  47. Fink M., Weinhüsel A., Niederle B., Haas O. A. Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. "Study Group Multiple Endocrine Neoplasia Austria (SMENA)". Int J Cancer. 1996 Aug 22;69(4):312–316. doi: 10.1002/(SICI)1097-0215(19960822)69:4<312::AID-IJC13>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  48. Fitze G., Schreiber M., Kuhlisch E., Schackert H. K., Roesner D. Association of RET protooncogene codon 45 polymorphism with Hirschsprung disease. Am J Hum Genet. 1999 Nov;65(5):1469–1473. doi: 10.1086/302618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Frank-Raue K., Höppner W., Frilling A., Kotzerke J., Dralle H., Haase R., Mann K., Seif F., Kirchner R., Rendl J. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group. J Clin Endocrinol Metab. 1996 May;81(5):1780–1783. doi: 10.1210/jcem.81.5.8626834. [DOI] [PubMed] [Google Scholar]
  50. Gagel R. F. Pheochromocytoma, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1994 Apr 14;330(15):1090–1091. doi: 10.1056/nejm199404143301518. [DOI] [PubMed] [Google Scholar]
  51. Gash D. M., Zhang Z., Ovadia A., Cass W. A., Yi A., Simmerman L., Russell D., Martin D., Lapchak P. A., Collins F. Functional recovery in parkinsonian monkeys treated with GDNF. Nature. 1996 Mar 21;380(6571):252–255. doi: 10.1038/380252a0. [DOI] [PubMed] [Google Scholar]
  52. Gimm O., Marsh D. J., Andrew S. D., Frilling A., Dahia P. L., Mulligan L. M., Zajac J. D., Robinson B. G., Eng C. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab. 1997 Nov;82(11):3902–3904. doi: 10.1210/jcem.82.11.4508. [DOI] [PubMed] [Google Scholar]
  53. Gimm O., Neuberg D. S., Marsh D. J., Dahia P. L., Hoang-Vu C., Raue F., Hinze R., Dralle H., Eng C. Over-representation of a germline RET sequence variant in patients with sporadic medullary thyroid carcinoma and somatic RET codon 918 mutation. Oncogene. 1999 Feb 11;18(6):1369–1373. doi: 10.1038/sj.onc.1202418. [DOI] [PubMed] [Google Scholar]
  54. Gorlin R. J., Sedano H. O., Vickers R. A., Cervenka J. Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid--a syndrome. Cancer. 1968 Aug;22(2):293–passim. doi: 10.1002/1097-0142(196808)22:2<293::aid-cncr2820220206>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  55. Hofstra R. M., Cheng N. C., Hansen C., Stulp R. P., Stelwagen T., Clausen N., Tommerup N., Caron H., Westerveld A., Versteeg R. No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma. Hum Genet. 1996 Mar;97(3):362–364. doi: 10.1007/BF02185773. [DOI] [PubMed] [Google Scholar]
  56. Hofstra R. M., Fattoruso O., Quadro L., Wu Y., Libroia A., Verga U., Colantuoni V., Buys C. H. A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab. 1997 Dec;82(12):4176–4178. doi: 10.1210/jcem.82.12.4439. [DOI] [PubMed] [Google Scholar]
  57. Hofstra R. M., Landsvater R. M., Ceccherini I., Stulp R. P., Stelwagen T., Luo Y., Pasini B., Höppener J. W., van Amstel H. K., Romeo G. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994 Jan 27;367(6461):375–376. doi: 10.1038/367375a0. [DOI] [PubMed] [Google Scholar]
  58. Howe J. R., Norton J. A., Wells S. A., Jr Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery. 1993 Dec;114(6):1070–1077. [PubMed] [Google Scholar]
  59. Höppner W., Dralle H., Brabant G. Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A. Hum Mutat. 1998;Suppl 1:S128–S130. doi: 10.1002/humu.1380110143. [DOI] [PubMed] [Google Scholar]
  60. Höppner W., Ritter M. M. A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. Hum Mol Genet. 1997 Apr;6(4):587–590. doi: 10.1093/hmg/6.4.587. [DOI] [PubMed] [Google Scholar]
  61. Ishiguro Y., Iwashita T., Murakami H., Asai N., Iida K., Goto H., Hayakawa T., Takahashi M. The role of amino acids surrounding tyrosine 1062 in ret in specific binding of the shc phosphotyrosine-binding domain. Endocrinology. 1999 Sep;140(9):3992–3998. doi: 10.1210/endo.140.9.7003. [DOI] [PubMed] [Google Scholar]
  62. Ito S., Iwashita T., Asai N., Murakami H., Iwata Y., Sobue G., Takahashi M. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870–2872. [PubMed] [Google Scholar]
  63. Ivanchuk S. M., Myers S. M., Eng C., Mulligan L. M. De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Hum Mol Genet. 1996 Dec;5(12):2023–2026. doi: 10.1093/hmg/5.12.2023. [DOI] [PubMed] [Google Scholar]
  64. Ivanchuk S. M., Myers S. M., Mulligan L. M. Expression of RET 3' splicing variants during human kidney development. Oncogene. 1998 Feb 26;16(8):991–996. doi: 10.1038/sj.onc.1201622. [DOI] [PubMed] [Google Scholar]
  65. Iwamoto T., Taniguchi M., Asai N., Ohkusu K., Nakashima I., Takahashi M. cDNA cloning of mouse ret proto-oncogene and its sequence similarity to the cadherin superfamily. Oncogene. 1993 Apr;8(4):1087–1091. [PubMed] [Google Scholar]
  66. Iwashita T., Asai N., Murakami H., Matsuyama M., Takahashi M. Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutation. Oncogene. 1996 Feb 1;12(3):481–487. [PubMed] [Google Scholar]
  67. Iwashita T., Kato M., Murakami H., Asai N., Ishiguro Y., Ito S., Iwata Y., Kawai K., Asai M., Kurokawa K. Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. Oncogene. 1999 Jul 1;18(26):3919–3922. doi: 10.1038/sj.onc.1202742. [DOI] [PubMed] [Google Scholar]
  68. Iwashita T., Murakami H., Asai N., Takahashi M. Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain. Hum Mol Genet. 1996 Oct;5(10):1577–1580. doi: 10.1093/hmg/5.10.1577. [DOI] [PubMed] [Google Scholar]
  69. Iwashita T., Murakami H., Kurokawa K., Kawai K., Miyauchi A., Futami H., Qiao S., Ichihara M., Takahashi M. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun. 2000 Feb 24;268(3):804–808. doi: 10.1006/bbrc.2000.2227. [DOI] [PubMed] [Google Scholar]
  70. Jhiang S. M., Mazzaferri E. L. The ret/PTC oncogene in papillary thyroid carcinoma. J Lab Clin Med. 1994 Mar;123(3):331–337. [PubMed] [Google Scholar]
  71. Jing S., Wen D., Yu Y., Holst P. L., Luo Y., Fang M., Tamir R., Antonio L., Hu Z., Cupples R. GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell. 1996 Jun 28;85(7):1113–1124. doi: 10.1016/s0092-8674(00)81311-2. [DOI] [PubMed] [Google Scholar]
  72. Komminoth P., Kunz E. K., Matias-Guiu X., Hiort O., Christiansen G., Colomer A., Roth J., Heitz P. U. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary thyroid carcinomas. Cancer. 1995 Aug 1;76(3):479–489. doi: 10.1002/1097-0142(19950801)76:3<479::aid-cncr2820760319>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  73. Komminoth P., Roth J., Muletta-Feurer S., Saremaslani P., Seelentag W. K., Heitz P. U. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. J Clin Endocrinol Metab. 1996 Jun;81(6):2041–2046. doi: 10.1210/jcem.81.6.8964826. [DOI] [PubMed] [Google Scholar]
  74. Lin L. F., Doherty D. H., Lile J. D., Bektesh S., Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993 May 21;260(5111):1130–1132. doi: 10.1126/science.8493557. [DOI] [PubMed] [Google Scholar]
  75. Lips C. J., Landsvater R. M., Höppener J. W., Geerdink R. A., Blijham G., van Veen J. M., van Gils A. P., de Wit M. J., Zewald R. A., Berends M. J. Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med. 1994 Sep 29;331(13):828–835. doi: 10.1056/NEJM199409293311302. [DOI] [PubMed] [Google Scholar]
  76. Liu X., Vega Q. C., Decker R. A., Pandey A., Worby C. A., Dixon J. E. Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. J Biol Chem. 1996 Mar 8;271(10):5309–5312. doi: 10.1074/jbc.271.10.5309. [DOI] [PubMed] [Google Scholar]
  77. Lorenzo M. J., Gish G. D., Houghton C., Stonehouse T. J., Pawson T., Ponder B. A., Smith D. P. RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2. Oncogene. 1997 Feb 20;14(7):763–771. doi: 10.1038/sj.onc.1200894. [DOI] [PubMed] [Google Scholar]
  78. Marsh D. J., McDowall D., Hyland V. J., Andrew S. D., Schnitzler M., Gaskin E. L., Nevell D. F., Diamond T., Delbridge L., Clifton-Bligh P. The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2A families. Clin Endocrinol (Oxf) 1996 Feb;44(2):213–220. doi: 10.1046/j.1365-2265.1996.505292.x. [DOI] [PubMed] [Google Scholar]
  79. Marshall G. M., Peaston A. E., Hocker J. E., Smith S. A., Hansford L. M., Tobias V., Norris M. D., Haber M., Smith D. P., Lorenzo M. J. Expression of multiple endocrine neoplasia 2B RET in neuroblastoma cells alters cell adhesion in vitro, enhances metastatic behavior in vivo, and activates Jun kinase. Cancer Res. 1997 Dec 1;57(23):5399–5405. [PubMed] [Google Scholar]
  80. Meng X., Lindahl M., Hyvönen M. E., Parvinen M., de Rooij D. G., Hess M. W., Raatikainen-Ahokas A., Sainio K., Rauvala H., Lakso M. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science. 2000 Feb 25;287(5457):1489–1493. doi: 10.1126/science.287.5457.1489. [DOI] [PubMed] [Google Scholar]
  81. Miyauchi A., Futami H., Hai N., Yokozawa T., Kuma K., Aoki N., Kosugi S., Sugano K., Yamaguchi K. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res. 1999 Jan;90(1):1–5. doi: 10.1111/j.1349-7006.1999.tb00658.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Mulligan L. M., Eng C., Attié T., Lyonnet S., Marsh D. J., Hyland V. J., Robinson B. G., Frilling A., Verellen-Dumoulin C., Safar A. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet. 1994 Dec;3(12):2163–2167. doi: 10.1093/hmg/3.12.2163. [DOI] [PubMed] [Google Scholar]
  83. Mulligan L. M., Eng C., Healey C. S., Clayton D., Kwok J. B., Gardner E., Ponder M. A., Frilling A., Jackson C. E., Lehnert H. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994 Jan;6(1):70–74. doi: 10.1038/ng0194-70. [DOI] [PubMed] [Google Scholar]
  84. Mulligan L. M., Kwok J. B., Healey C. S., Elsdon M. J., Eng C., Gardner E., Love D. R., Mole S. E., Moore J. K., Papi L. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993 Jun 3;363(6428):458–460. doi: 10.1038/363458a0. [DOI] [PubMed] [Google Scholar]
  85. Mulligan L. M., Marsh D. J., Robinson B. G., Schuffenecker I., Zedenius J., Lips C. J., Gagel R. F., Takai S. I., Noll W. W., Fink M. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med. 1995 Oct;238(4):343–346. doi: 10.1111/j.1365-2796.1995.tb01208.x. [DOI] [PubMed] [Google Scholar]
  86. Mulligan L. M., Timmer T., Ivanchuk S. M., Campling B. G., Young L. C., Rabbitts P. H., Sundaresan V., Hofstra R. M., Eng C. Investigation of the genes for RET and its ligand complex, GDNF/GFR alpha-I, in small cell lung carcinoma. Genes Chromosomes Cancer. 1998 Apr;21(4):326–332. [PubMed] [Google Scholar]
  87. Murakami H., Iwashita T., Asai N., Iwata Y., Narumiya S., Takahashi M. Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinase. Oncogene. 1999 Mar 18;18(11):1975–1982. doi: 10.1038/sj.onc.1202514. [DOI] [PubMed] [Google Scholar]
  88. Murakami H., Iwashita T., Asai N., Shimono Y., Iwata Y., Kawai K., Takahashi M. Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation. Biochem Biophys Res Commun. 1999 Aug 19;262(1):68–75. doi: 10.1006/bbrc.1999.1186. [DOI] [PubMed] [Google Scholar]
  89. Myers S. M., Eng C., Ponder B. A., Mulligan L. M. Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene. 1995 Nov 16;11(10):2039–2045. [PubMed] [Google Scholar]
  90. Myers S. M., Salomon R., Goessling A., Pelet A., Eng C., von Deimling A., Lyonnet S., Mulligan L. M. Investigation of germline GFR alpha-1 mutations in Hirschsprung disease. J Med Genet. 1999 Mar;36(3):217–220. [PMC free article] [PubMed] [Google Scholar]
  91. Ohiwa M., Murakami H., Iwashita T., Asai N., Iwata Y., Imai T., Funahashi H., Takagi H., Takahashi M. Characterization of Ret-Shc-Grb2 complex induced by GDNF, MEN 2A, and MEN 2B mutations. Biochem Biophys Res Commun. 1997 Aug 28;237(3):747–751. doi: 10.1006/bbrc.1997.7225. [DOI] [PubMed] [Google Scholar]
  92. Onochie C. I., Korngut L. M., Vanhorne J. B., Myers S. M., Michaud D., Mulligan L. M. Characterisation of the human GFRalpha-3 locus and investigation of the gene in Hirschsprung disease. J Med Genet. 2000 Sep;37(9):674–679. doi: 10.1136/jmg.37.9.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Pachnis V., Mankoo B., Costantini F. Expression of the c-ret proto-oncogene during mouse embryogenesis. Development. 1993 Dec;119(4):1005–1017. doi: 10.1242/dev.119.4.1005. [DOI] [PubMed] [Google Scholar]
  94. Pandey A., Duan H., Di Fiore P. P., Dixit V. M. The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10. J Biol Chem. 1995 Sep 15;270(37):21461–21463. doi: 10.1074/jbc.270.37.21461. [DOI] [PubMed] [Google Scholar]
  95. Pasini A., Geneste O., Legrand P., Schlumberger M., Rossel M., Fournier L., Rudkin B. B., Schuffenecker I., Lenoir G. M., Billaud M. Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain. Oncogene. 1997 Jul 24;15(4):393–402. doi: 10.1038/sj.onc.1201199. [DOI] [PubMed] [Google Scholar]
  96. Passarge E. The genetics of Hirschsprung's disease. Evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med. 1967 Jan 19;276(3):138–143. doi: 10.1056/NEJM196701192760303. [DOI] [PubMed] [Google Scholar]
  97. Pigny P., Bauters C., Wemeau J. L., Houcke M. L., Crepin M., Caron P., Giraud S., Calender A., Buisine M. P., Kerckaert J. P. A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 1999 May;84(5):1700–1704. doi: 10.1210/jcem.84.5.5665. [DOI] [PubMed] [Google Scholar]
  98. Rabes H. M., Demidchik E. P., Sidorow J. D., Lengfelder E., Beimfohr C., Hoelzel D., Klugbauer S. Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res. 2000 Mar;6(3):1093–1103. [PubMed] [Google Scholar]
  99. Romano A., Wong W. T., Santoro M., Wirth P. J., Thorgeirsson S. S., Di Fiore P. P. The high transforming potency of erbB-2 and ret is associated with phosphorylation of paxillin and a 23 kDa protein. Oncogene. 1994 Oct;9(10):2923–2933. [PubMed] [Google Scholar]
  100. Rosenblad C., Grønborg M., Hansen C., Blom N., Meyer M., Johansen J., Dagø L., Kirik D., Patel U. A., Lundberg C. In vivo protection of nigral dopamine neurons by lentiviral gene transfer of the novel GDNF-family member neublastin/artemin. Mol Cell Neurosci. 2000 Feb;15(2):199–214. doi: 10.1006/mcne.1999.0817. [DOI] [PubMed] [Google Scholar]
  101. Rossel M., Pasini A., Chappuis S., Geneste O., Fournier L., Schuffenecker I., Takahashi M., van Grunsven L. A., Urdiales J. L., Rudkin B. B. Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations. Oncogene. 1997 Jan 23;14(3):265–275. doi: 10.1038/sj.onc.1200831. [DOI] [PubMed] [Google Scholar]
  102. Salomon R., Attié T., Pelet A., Bidaud C., Eng C., Amiel J., Sarnacki S., Goulet O., Ricour C., Nihoul-Fékété C. Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nat Genet. 1996 Nov;14(3):345–347. doi: 10.1038/ng1196-345. [DOI] [PubMed] [Google Scholar]
  103. Sancandi M., Ceccherini I., Costa M., Fava M., Chen B., Wu Y., Hofstra R., Laurie T., Griffths M., Burge D. Incidence of RET mutations in patients with Hirschsprung's disease. J Pediatr Surg. 2000 Jan;35(1):139–143. doi: 10.1016/s0022-3468(00)80031-7. [DOI] [PubMed] [Google Scholar]
  104. Santoro M., Carlomagno F., Romano A., Bottaro D. P., Dathan N. A., Grieco M., Fusco A., Vecchio G., Matoskova B., Kraus M. H. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381–383. doi: 10.1126/science.7824936. [DOI] [PubMed] [Google Scholar]
  105. Santoro M., Wong W. T., Aroca P., Santos E., Matoskova B., Grieco M., Fusco A., di Fiore P. P. An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway. Mol Cell Biol. 1994 Jan;14(1):663–675. doi: 10.1128/mcb.14.1.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Schimke R. N. Genetic aspects of multiple endocrine neoplasia. Annu Rev Med. 1984;35:25–31. doi: 10.1146/annurev.me.35.020184.000325. [DOI] [PubMed] [Google Scholar]
  107. Schneider R. The human protooncogene ret: a communicative cadherin? Trends Biochem Sci. 1992 Nov;17(11):468–469. doi: 10.1016/0968-0004(92)90490-z. [DOI] [PubMed] [Google Scholar]
  108. Schuchardt A., D'Agati V., Larsson-Blomberg L., Costantini F., Pachnis V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature. 1994 Jan 27;367(6461):380–383. doi: 10.1038/367380a0. [DOI] [PubMed] [Google Scholar]
  109. Schuffenecker I., Virally-Monod M., Brohet R., Goldgar D., Conte-Devolx B., Leclerc L., Chabre O., Boneu A., Caron J., Houdent C. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine. J Clin Endocrinol Metab. 1998 Feb;83(2):487–491. doi: 10.1210/jcem.83.2.4529. [DOI] [PubMed] [Google Scholar]
  110. Segouffin-Cariou C., Billaud M. Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J Biol Chem. 2000 Feb 4;275(5):3568–3576. doi: 10.1074/jbc.275.5.3568. [DOI] [PubMed] [Google Scholar]
  111. Smith D. P., Houghton C., Ponder B. A. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene. 1997 Sep 4;15(10):1213–1217. doi: 10.1038/sj.onc.1201481. [DOI] [PubMed] [Google Scholar]
  112. Soler R. M., Dolcet X., Encinas M., Egea J., Bayascas J. R., Comella J. X. Receptors of the glial cell line-derived neurotrophic factor family of neurotrophic factors signal cell survival through the phosphatidylinositol 3-kinase pathway in spinal cord motoneurons. J Neurosci. 1999 Nov 1;19(21):9160–9169. doi: 10.1523/JNEUROSCI.19-21-09160.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Songyang Z., Carraway K. L., 3rd, Eck M. J., Harrison S. C., Feldman R. A., Mohammadi M., Schlessinger J., Hubbard S. R., Smith D. P., Eng C. Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature. 1995 Feb 9;373(6514):536–539. doi: 10.1038/373536a0. [DOI] [PubMed] [Google Scholar]
  114. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol. 1996 May;14(5):1730–1740. doi: 10.1200/JCO.1996.14.5.1730. [DOI] [PubMed] [Google Scholar]
  115. Svensson P. J., Anvret M., Molander M. L., Nordenskjöld A. Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B). Hum Genet. 1998 Aug;103(2):145–148. doi: 10.1007/s004390050797. [DOI] [PubMed] [Google Scholar]
  116. Svensson P. J., Molander M. L., Eng C., Anvret M., Nordenskjöld A. Low frequency of RET mutations in Hirschsprung disease in Sweden. Clin Genet. 1998 Jul;54(1):39–44. doi: 10.1111/j.1399-0004.1998.tb03691.x. [DOI] [PubMed] [Google Scholar]
  117. Tahira T., Ishizaka Y., Itoh F., Sugimura T., Nagao M. Characterization of ret proto-oncogene mRNAs encoding two isoforms of the protein product in a human neuroblastoma cell line. Oncogene. 1990 Jan;5(1):97–102. [PubMed] [Google Scholar]
  118. Takahashi M., Buma Y., Hiai H. Isolation of ret proto-oncogene cDNA with an amino-terminal signal sequence. Oncogene. 1989 Jun;4(6):805–806. [PubMed] [Google Scholar]
  119. Takahashi M., Buma Y., Iwamoto T., Inaguma Y., Ikeda H., Hiai H. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene. 1988 Nov;3(5):571–578. [PubMed] [Google Scholar]
  120. Takahashi M., Iwashita T., Santoro M., Lyonnet S., Lenoir G. M., Billaud M. Co-segregation of MEN2 and Hirschsprung's disease: the same mutation of RET with both gain and loss-of-function? Hum Mutat. 1999;13(4):331–336. doi: 10.1002/(SICI)1098-1004(1999)13:4<331::AID-HUMU11>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  121. Telander R. L., Zimmerman D., Sizemore G. W., van Heerden J. A., Grant C. S. Medullary carcinoma in children. Results of early detection and surgery. Arch Surg. 1989 Jul;124(7):841–843. doi: 10.1001/archsurg.1989.01410070099020. [DOI] [PubMed] [Google Scholar]
  122. Treanor J. J., Goodman L., de Sauvage F., Stone D. M., Poulsen K. T., Beck C. D., Gray C., Armanini M. P., Pollock R. A., Hefti F. Characterization of a multicomponent receptor for GDNF. Nature. 1996 Jul 4;382(6586):80–83. doi: 10.1038/382080a0. [DOI] [PubMed] [Google Scholar]
  123. Wohllk N., Cote G. J., Bugalho M. M., Ordonez N., Evans D. B., Goepfert H., Khorana S., Schultz P., Richards C. S., Gagel R. F. Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab. 1996 Oct;81(10):3740–3745. doi: 10.1210/jcem.81.10.8855832. [DOI] [PubMed] [Google Scholar]
  124. Xing S., Smanik P. A., Oglesbee M. J., Trosko J. E., Mazzaferri E. L., Jhiang S. M. Characterization of ret oncogenic activation in MEN2 inherited cancer syndromes. Endocrinology. 1996 May;137(5):1512–1519. doi: 10.1210/endo.137.5.8612479. [DOI] [PubMed] [Google Scholar]
  125. van Weering D. H., Bos J. L. Glial cell line-derived neurotrophic factor induces Ret-mediated lamellipodia formation. J Biol Chem. 1997 Jan 3;272(1):249–254. doi: 10.1074/jbc.272.1.249. [DOI] [PubMed] [Google Scholar]
  126. van Weering D. H., Medema J. P., van Puijenbroek A., Burgering B. M., Baas P. D., Bos J. L. Ret receptor tyrosine kinase activates extracellular signal-regulated kinase 2 in SK-N-MC cells. Oncogene. 1995 Dec 7;11(11):2207–2214. [PubMed] [Google Scholar]
  127. van Weering D. H., de Rooij J., Marte B., Downward J., Bos J. L., Burgering B. M. Protein kinase B activation and lamellipodium formation are independent phosphoinositide 3-kinase-mediated events differentially regulated by endogenous Ras. Mol Cell Biol. 1998 Apr;18(4):1802–1811. doi: 10.1128/mcb.18.4.1802. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES