RET and MEN2 This presentation brought to you by Meredith Stewart

The Disease: MEN = Multiple endocrine neoplasia

MEN 2 Cancers Familial Medullary Thyroid Carcinoma Familial Medullary Thyroid Carcinoma MEN 2A MEN 2A MEN 2B MEN 2B Medullary thyroid carcinoma (C cells) Medullary thyroid carcinoma (C cells) Pheochromocytoma (adrenal tumors) Pheochromocytoma (adrenal tumors) Parathyroid hyperplasia Parathyroid hyperplasia

Autosomal dominant inheritance Autosomal dominant inheritance Nearly 100 % penetrance Nearly 100 % penetrance 1 case out of 30,000 – 50,000 people 1 case out of 30,000 – 50,000 people Treatment options: Treatment options: –Remove the thyroid –Inhibit malfunctioning protein’s action MEN 2 Cancer, con’t:

RET = The Bad Guy (Rearranged during Transfection) Proto-oncogene Proto-oncogene Receptor tyrosine kinase Receptor tyrosine kinase

RET = The Bad Guy (Rearranged during Transfection) Proto-oncogene Proto-oncogene Receptor tyrosine kinase Receptor tyrosine kinase One of pathways is in fact Ras  MAPK One of pathways is in fact Ras  MAPK

Many paths to follow…

A less detailed view Coreceptor = GFRα family Coreceptor = GFRα family Ligand = GFL family Ligand = GFL family Cysteine region autophosphorylates when bound by ligand Cysteine region autophosphorylates when bound by ligand Phosphorylates other substrates Phosphorylates other substrates

“The activation of the RET pathway results in increased cell motility, dissociation of cell adhesion, and the migration towards a localized source of GDNF. Cellular responses to RET include the formation of lamellipodia, filopodia, and reorganization of the actin cytoskeleton.” -Tang, Worley, Sanicola and Dressler, 1998 Normal RET Function?

Homozygous knockouts have no kidneys!!! Knockout Mice

Normal RET Function? Homozygous knockouts have no kidneys!!! Knockout Mice

“The activation of the RET pathway results in increased cell motility, dissociation of cell adhesion, and the migration towards a localized source of GDNF. ” -Tang, Worley, Sanicola and Dressler, 1998 …such as a ureteric bud growing towards some mesenchymal cells to form kidneys… Normal RET Function?

RET expressed at different points of development of organism (and differently in organism) RET expressed at different points of development of organism (and differently in organism)

What goes wrong in cancer? Proto-oncogene  constituvely active Proto-oncogene  constituvely active

What goes wrong in cancer? Proto-oncogene  constituvely active Proto-oncogene  constituvely active FMTC: cysteine mutation (extracellular domain) FMTC: cysteine mutation (extracellular domain) MEN 2A: cysteine mutation at codon 634 MEN 2A: cysteine mutation at codon 634

What goes wrong in cancer? Proto-oncogene  constituvely active Proto-oncogene  constituvely active FMTC: cysteine mutation (extracellular domain) FMTC: cysteine mutation (extracellular domain) MEN 2A: cysteine mutation at codon 634 MEN 2A: cysteine mutation at codon 634 MEN 2B: kinase mutation at codon 918 MEN 2B: kinase mutation at codon 918

When RET goes bad… Loss of function RET leads to Hirschsprung disease (recessive) Loss of function RET leads to Hirschsprung disease (recessive) Overactive RET can also lead to papillary thryoid cancer Overactive RET can also lead to papillary thryoid cancer

BUT LOOK!!! Washington University School of Medicine performed this experiment: The third eye shown was treated during development with kinase inhibitor zd6474 and mostly rescued Normal RETToo much RETToo much RET + zd6474

Works Referenced L. Alberti, C. Carniti, C. Miranda, E. Roccatto, and M. Pierotti. “RET and NRTK1 Proto- Oncogenes in Human Diseases.” Journal of Cellular Physiology 195 (2003): 168—186. L. Alberti, C. Carniti, C. Miranda, E. Roccatto, and M. Pierotti. “RET and NRTK1 Proto- Oncogenes in Human Diseases.” Journal of Cellular Physiology 195 (2003): 168—186. J. Hansford and L. Mulligan. “Multiple endocrine neoplasia type 2 and RET: from neoplasia and neurogenesis.” Journal of Medical Genetics 37 (2003): 817—827. J. Hansford and L. Mulligan. “Multiple endocrine neoplasia type 2 and RET: from neoplasia and neurogenesis.” Journal of Medical Genetics 37 (2003): 817—827. Hofstra, Robert M.W. “The RET gene and its associated diseases.” Diss. Department of Medical Genetics, University of Groningen. Netherlands: —19. Accessed at Hofstra, Robert M.W. “The RET gene and its associated diseases.” Diss. Department of Medical Genetics, University of Groningen. Netherlands: —19. Accessed at M. Ichihara, Y. Murakumo, and M. Takahashi. “RET and neuroendocrine tumors.” Cancer Letters 204 (2004): 197—211. M. Ichihara, Y. Murakumo, and M. Takahashi. “RET and neuroendocrine tumors.” Cancer Letters 204 (2004): 197—211. S. Manie, M. Santoro, A. Fusco and M. Billaud. “The RET receptor: function in development and dysfunction in congenital malformation.” TRENDS in Genetics 17 (2001): 580—589. S. Manie, M. Santoro, A. Fusco and M. Billaud. “The RET receptor: function in development and dysfunction in congenital malformation.” TRENDS in Genetics 17 (2001): 580—589. M. Tang, D. Worley, M. Sanicola, and G. Dressler. “The RET-Glial Cell-derived Neurotrophic Factor (GDNF) Pathway Stimulates Migration and Chemoattraction of Epithelial Cells.” The Journal of Cell Biology 142 (1998): 1337—1345. M. Tang, D. Worley, M. Sanicola, and G. Dressler. “The RET-Glial Cell-derived Neurotrophic Factor (GDNF) Pathway Stimulates Migration and Chemoattraction of Epithelial Cells.” The Journal of Cell Biology 142 (1998): 1337—1345. M. Vidal, S. Wells, R. Anderson, and R. Cagan. “ZD6474 Suppresses Oncogenic RET Isoforms in a Drosophila Model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma.” Cancer Research 65 (2005): 3538—3541. M. Vidal, S. Wells, R. Anderson, and R. Cagan. “ZD6474 Suppresses Oncogenic RET Isoforms in a Drosophila Model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma.” Cancer Research 65 (2005): 3538—3541. (Basic information about different types of cancer was searched for at (Basic information about different types of cancer was searched for at