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

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

3. Multiple Endocrine Neoplasia Type 2 Thyroid Cancer Thyroid Cancer Germ line point mutations in RET gene. Germ line point mutations in RET gene. Cause over activation of RET Cause over activation of RET Triggers proliferation in endocrine cells. 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 Gene on chromosome 10 q 11.2 Encodes a receptor tyrosine kinase Encodes a receptor tyrosine kinase Required for maturation of nervous system and kidney morphogenesis 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: Co-receptors: GFR  1, 2, 3, & 4 GFR  1, 2, 3, & 4 Growth Factor Ligands: Growth Factor Ligands: GDNF, NRTN, ARTN, PSPN GDNF, NRTN, ARTN, PSPN

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

9. RET Proto-Oncogene in MEN Type 2 Germline point mutations of RET are responsible for all Forms of MEN Type MEN 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. 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. Ligand independent dimerization, activation, and transformation. Constitutive Phosphorylation of intracellular proteins. Constitutive Phosphorylation of intracellular proteins. Overactive Signaling Overactive Signaling

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

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 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 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 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 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 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