Tumor Biology

, Volume 36, Issue 3, pp 1423–1428 | Cite as

Mutation-introduced dimerization of receptor tyrosine kinases: from protein structure aberrations to carcinogenesis

  • Huimin Hu
  • Yanwei Liu
  • Tao JiangEmail author


Cancer is the greatest challenge to human health in our era. Perturbations of receptor tyrosine kinase (RTK) function contribute to a large chunk of cancer etiology. Current evidence supports that mutations in RTKs mediate receptor dimerization and result in ligand-independent kinase activity and tumorigenesis, indicating that mutation-introduced receptor dimerization is a critical component of oncogenesis RTK mutations. However, there are no specialized reviews of this important principle. In the current review, we discuss the physiological and harmless RTK function and subsequently examine mutation-introduced dimerization of RTKs and the role of these mutations in tumorigenesis. We also summarize the protein structure characteristics that are important for dimerization and introduce research methods and tools to predict and validate the existence of oncogenic mutations introduced by dimerization in RTKs.


Receptor tyrosine kinases Mutation Dimerization Oncogenicity Gene rearrangement Protein structure alteration Oncogenesis 



This study was supported by grants from the National High Technology Research and Development Program (No. 2012AA02A508), the National 973 program (No. 2011CB707804), and the National Nature Science Foundation of China (No. 81201993 and No. 81272804).

Conflicts of interest



  1. 1.
    Dent P. Met in lung cancer. Cancer Biol Ther. 2014;15(6):653–4.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Schlessinger J, Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron. 1992;9(3):383–91.CrossRefPubMedGoogle Scholar
  3. 3.
    Assoian RK, Schwartz MA. Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression. Curr Opin Genet Dev. 2001;11(1):48–53.CrossRefPubMedGoogle Scholar
  4. 4.
    Hieronymus T, Zenke M, Baek JH, et al. The clash of Langerhans cell homeostasis in skin: Should I stay or should I go? Semin Cell Dev Biol. 2014. doi: 10.1016/j.semcdb.2014.02.009
  5. 5.
    Fogh BS, Multhaupt HA, Couchman JR. Protein kinase C, focal adhesions and the regulation of cell migration. J Histochem Cytochem. 2014;62(3):172–84.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Witsch E, Sela M, Yarden Y. Roles for growth factors in cancer progression. Physiology (Bethesda). 2010;25(2):85–101.CrossRefGoogle Scholar
  7. 7.
    Yarden Y, Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443–78.CrossRefPubMedGoogle Scholar
  8. 8.
    Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61(2):203–12.CrossRefPubMedGoogle Scholar
  9. 9.
    Maleszka R, Mason PH, Barron AB. Epigenomics and the concept of degeneracy in biological systems. Brief Funct Genomics. 2014;13(3):191–202.CrossRefPubMedGoogle Scholar
  10. 10.
    Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988;241(4861):42–52.CrossRefPubMedGoogle Scholar
  11. 11.
    Locascio LE, Donoghue DJ. KIDs rule: regulatory phosphorylation of RTKs. Trends Biochem Sci. 2013;38(2):75–84.CrossRefPubMedGoogle Scholar
  12. 12.
    Yamanashi Y, Tezuka T, Yokoyama K. Activation of receptor protein-tyrosine kinases from the cytoplasmic compartment. J Biochem. 2012;151(4):353–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2000;103(2):211–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Wong AJ et al. Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proc Natl Acad Sci U S A. 1987;84(19):6899–903.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jeuken J et al. Robust detection of EGFR copy number changes and EGFR variant III: technical aspects and relevance for glioma diagnostics. Brain Pathol. 2009;19(4):661–71.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Choura M, Rebai A. Receptor tyrosine kinases: from biology to pathology. J Recept Signal Transduct Res. 2011;31(6):387–94.CrossRefPubMedGoogle Scholar
  17. 17.
    Park M et al. Mechanism of met oncogene activation. Cell. 1986;45(6):895–904.CrossRefPubMedGoogle Scholar
  18. 18.
    Amicone L et al. Transgenic expression in the liver of truncated Met blocks apoptosis and permits immortalization of hepatocytes. EMBO J. 1997;16(3):495–503.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Liang TJ et al. Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors. J Clin Invest. 1996;97(12):2872–7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rodrigues GA, Park M. Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase. Mol Cell Biol. 1993;13(11):6711–22.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest. 2002;109(7):863–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Garrett TP et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor alpha. Cell. 2002;110(6):763–73.CrossRefPubMedGoogle Scholar
  23. 23.
    Cohen-Katsenelson K et al. Identification and analysis of a novel dimerization domain shared by various members of c-Jun N-terminal kinase (JNK) scaffold proteins. J Biol Chem. 2013;288(10):7294–304.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Cappellen D et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999;23(1):18–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Naski MC et al. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nat Genet. 1996;13(2):233–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Kannan K, Givol D. FGF receptor mutations: dimerization syndromes, cell growth suppression, and animal models. IUBMB Life. 2000;49(3):197–205.CrossRefPubMedGoogle Scholar
  27. 27.
    Liao RG et al. Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma. Cancer Res. 2013;73(16):5195–205.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Roskoski RJ. Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition. Pharmacol Res. 2013;68(1):68–94.CrossRefPubMedGoogle Scholar
  29. 29.
    Stoica GE et al. Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J Biol Chem. 2002;277(39):35990–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Stoica GE et al. Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem. 2001;276(20):16772–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Shackelford RE et al. ALK-rearrangements and testing methods in non-small cell lung cancer: a review. Genes Cancer. 2014;5(1–2):1–14.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Takeuchi K et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14(20):6618–24.CrossRefPubMedGoogle Scholar
  33. 33.
    Lu X, Gross AW, Lodish HF. Active conformation of the erythropoietin receptor: random and cysteine-scanning mutagenesis of the extracellular juxtamembrane and transmembrane domains. J Biol Chem. 2006;281(11):7002–11.CrossRefPubMedGoogle Scholar
  34. 34.
    Kjaer S et al. Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations. Oncogene. 2006;25(53):7086–95.CrossRefPubMedGoogle Scholar
  35. 35.
    Tong Q, Xing S, Jhiang SM. Leucine zipper-mediated dimerization is essential for the PTC1 oncogenic activity. J Biol Chem. 1997;272(14):9043–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Armon A, Graur D, Ben-Tal N. ConSurf: an algorithmic tool for the identification of functional regions in proteins by surface mapping of phylogenetic information. J Mol Biol. 2001;307(1):447–63.CrossRefPubMedGoogle Scholar
  37. 37.
    Glaser F et al. ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics. 2003;19(1):163–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Hu J et al. Differential roles of cysteine residues in the cellular trafficking, dimerization, and function of the high-density lipoprotein receptor. SR-BI. Biochemistry. 2011;50(50):10860–75.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kong-Beltran M, Stamos J, Wickramasinghe D. The Sema domain of Met is necessary for receptor dimerization and activation. Cancer Cell. 2004;6(1):75–84.CrossRefPubMedGoogle Scholar
  40. 40.
    Zenatti PP et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet. 2011;43(10):932–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Molecular Neuropathology, Beijing Neurosurgical InstituteCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Chinese Glioma Cooperative Group (CGCG)BeijingChina
  3. 3.Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  4. 4.Beijing Institute for Brain Disorders Brain Tumor CenterBeijingChina

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