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RET Proto- Oncogene in The Development of Thyroid Cancer: Multiple Endocrine Neoplasia Type 2

RET Proto- Oncogene in The Development of Thyroid Cancer: Multiple Endocrine Neoplasia Type 2. Courtney Brooks. Overview. MEN Type 2 RET Gene-Role in Normal Development Normal RET Signaling Pathway Mutations Responsible for MEN Type 2 Mutant RET Signaling Pathway

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RET Proto- Oncogene in The Development of Thyroid Cancer: Multiple Endocrine Neoplasia Type 2

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  1. RET Proto- Oncogene in The Development of Thyroid Cancer: Multiple Endocrine Neoplasia Type 2 Courtney Brooks

  2. Overview • MEN Type 2 • RET Gene-Role in Normal Development • Normal RET Signaling Pathway • Mutations Responsible for MEN Type 2 • Mutant RET Signaling Pathway • Diagnosis and Treatment for the Cancer

  3. Multiple Endocrine Neoplasia Type 2 • Thyroid Cancer • Germ line point mutations in RET gene. • Cause over activation of RET • Triggers proliferation in endocrine cells.

  4. 3 Forms of MEN Type 2 • MEN Type 2a • MEN Type 2b • FMTC

  5. RET • Gene on chromosome 10 q 11.2 • Encodes a receptor tyrosine kinase • Required for maturation of nervous system and kidney morphogenesis

  6. RET: Role in Normal Development RET deficient mice : Die shortly after birth Lack the Enteric Nervous System Display Renal Agenesis (no Kidney) Have Fewer Thyroid C Cells

  7. Components of the RET Signaling Pathway • Co-receptors: GFR  1,2, 3, & 4 • Growth Factor Ligands: GDNF, NRTN, ARTN, PSPN

  8. RET Cys GFR  1 Extracellular Domain GDNF Cys Cys Cys Cell Membrane P Intracellular Domain P RAS-RAF Pathway PI3 Kinase Pathway

  9. RET Proto-Oncogene in MEN Type 2 • Germline point mutations of RET are responsible for all Forms of MEN Type MEN 2 • The mutations affect either the extracellular or the intracellular tyrosine kinase domain of RET receptor.

  10. RET Gene Showing Mutations For MEN Type 2

  11. The Effects of Mutations on RET Function • Ligand independent dimerization, activation, and transformation. • Constitutive Phosphorylation of intracellular proteins. • Overactive Signaling

  12. RET Cys GFR  1 Cys Extracellular Domain Arg Cys Cell Membrane P P Intracellular Domain P P Over Active Signalling to Cells Uncontrolled Cell Proliferation

  13. Diagnosis and Management of MEN Type 2 • Genetic Screening for RET mutations • Thyrodectomy • New Therapeutic Strategies : Inhibitors specific for RET oncoproteins

  14. Sources • Albert, L. Carniti, C. RET and NTRK1. 2003. Proto-Oncogenes in Human Diseases. Journal of Cellular Physiology. 195: 168-186 • Manie, S. Santoro, M. 2001. The RET receptor: function in development and dysfunction in congenital malformation. Trends in Genetics. 17 (10): 580-589 • MEN Syndromes. 2000. www.endocrineweb.com/men/men2.html • Borello, MG, Mercalli E. 1995. RET activation by germline MEN 2A, and MEN 2 B mutations. Oncogene 11:2419-2427 • Mulligan LM, et al. Specific mutations of the RET proto-oncogene are related to MEN 2A and FMTC. Nat Genet. 1994; 6(1):70-4

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