ret and men2

RET and MEN2RET and MEN2

This presentation brought to This presentation brought to you by Meredith Stewartyou by Meredith Stewart

The Disease:The Disease:

MEN = Multiple endocrine neoplasiaMEN = Multiple endocrine neoplasia

MEN 2 CancersMEN 2 Cancers FFamilial amilial MMedullary edullary

TThyroid hyroid CCarcinoma arcinoma MEN 2AMEN 2A MEN 2BMEN 2B

Medullary thyroid Medullary thyroid carcinoma (C cells)carcinoma (C cells)Pheochromocytoma Pheochromocytoma (adrenal tumors)(adrenal tumors)Parathyroid hyperplasiaParathyroid hyperplasia

Autosomal dominant inheritanceAutosomal dominant inheritance Nearly 100 % penetranceNearly 100 % penetrance 1 case out of 30,000 – 50,000 people1 case out of 30,000 – 50,000 people

Treatment options:Treatment options:– Remove the thyroidRemove the thyroid– Inhibit malfunctioning protein’s actionInhibit malfunctioning protein’s action

MEN 2 Cancer, con’t:MEN 2 Cancer, con’t:

RET = The Bad RET = The Bad GuyGuy

((ReRearranged during arranged during TTransfection)ransfection)

Proto-oncogeneProto-oncogene Receptor tyrosine Receptor tyrosine

kinasekinase

RET = The Bad RET = The Bad GuyGuy

((ReRearranged during arranged during TTransfection)ransfection)

Proto-oncogeneProto-oncogene Receptor tyrosine kinaseReceptor tyrosine kinase One of pathways is in One of pathways is in

fact Ras fact Ras MAPK MAPK

Many paths to follow…Many paths to follow…

A less detailed viewA less detailed view

Coreceptor = GFRα Coreceptor = GFRα familyfamily

Ligand = GFL Ligand = GFL familyfamily

Cysteine region Cysteine region autophosphorylateautophosphorylates when bound by s when bound by ligandligand

Phosphorylates Phosphorylates other substratesother substrates

““The activation of the RET pathway The activation of the RET pathway results in increased cell motility, results in increased cell motility, dissociation of cell adhesion, and the dissociation of cell adhesion, and the migration towards a localized source of migration towards a localized source of GDNF. Cellular responses to RET GDNF. Cellular responses to RET include the formation of lamellipodia, include the formation of lamellipodia, filopodia, and reorganization of the filopodia, and reorganization of the actin cytoskeleton.”actin cytoskeleton.”

-Tang, Worley, Sanicola and Dressler, 1998-Tang, Worley, Sanicola and Dressler, 1998

Normal RET Function?Normal RET Function?


Homozygous Homozygous knockouts have no knockouts have no kidneys!!!kidneys!!!

Knockout MiceKnockout Mice

““The activation of the RET pathway The activation of the RET pathway results in results in increased cell increased cell motility, dissociation of cell motility, dissociation of cell adhesion, and the migration adhesion, and the migration towards a localized source of towards a localized source of GDNF.GDNF.””

-Tang, Worley, Sanicola and Dressler, 1998-Tang, Worley, Sanicola and Dressler, 1998

……such as a ureteric bud growing towards some such as a ureteric bud growing towards some mesenchymal cells to form kidneys…mesenchymal cells to form kidneys…



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

What goes wrong in cancer?What goes wrong in cancer?

Proto-oncogene Proto-oncogene constituvely activeconstituvely active



FMTC: cysteine mutation FMTC: cysteine mutation (extracellular domain)(extracellular domain)

MEN 2A: cysteine MEN 2A: cysteine mutation at codon 634mutation at codon 634



FMTC: cysteine mutation FMTC: cysteine mutation (extracellular domain)(extracellular domain)

MEN 2A: cysteine MEN 2A: cysteine mutation at codon 634mutation at codon 634

MEN 2B: kinase mutation MEN 2B: kinase mutation at codon 918at codon 918

When RET goes bad…When RET goes bad…

Loss of function RET leads to Loss of function RET leads to Hirschsprung disease (recessive)Hirschsprung disease (recessive)

Overactive RET can also lead to Overactive RET can also lead to papillary thryoid cancerpapillary thryoid cancer

BUT LOOK!!!BUT LOOK!!!

Washington University School of Medicine performed this Washington University School of Medicine performed this experiment:experiment:

The third eye shown was treated during The third eye shown was treated during development with kinase inhibitor zd6474 development with kinase inhibitor zd6474

and mostly rescuedand mostly rescued

Normal RET Too much RET

Too much RET + zd6474

Works ReferencedWorks Referenced

L. Alberti, C. Carniti, C. Miranda, E. Roccatto, and M. Pierotti. “RET and NRTK1 L. Alberti, C. Carniti, C. Miranda, E. Roccatto, and M. Pierotti. “RET and NRTK1 Proto-Oncogenes in Human Diseases.” Proto-Oncogenes in Human Diseases.” Journal of Cellular PhysiologyJournal of Cellular Physiology 195 195 (2003): 168—186.(2003): 168—186.

J. Hansford and L. Mulligan. “Multiple endocrine neoplasia type 2 and RET: from J. Hansford and L. Mulligan. “Multiple endocrine neoplasia type 2 and RET: from neoplasia and neurogenesis.” neoplasia and neurogenesis.” Journal of Medical GeneticsJournal of Medical Genetics 37 (2003): 817—827. 37 (2003): 817—827.

Hofstra, Robert M.W. “The RET gene and its associated diseases.” Diss. Hofstra, Robert M.W. “The RET gene and its associated diseases.” Diss. Department of Medical Genetics, University of Groningen. Netherlands: 1995. Department of Medical Genetics, University of Groningen. Netherlands: 1995. 15—19. Accessed at 15—19. Accessed at http://dissertations.ub.rug.nl/FILES/faculties/medicine/1995/r.m.w.hofstra/http://dissertations.ub.rug.nl/FILES/faculties/medicine/1995/r.m.w.hofstra/thesis.pdfthesis.pdf

M. Ichihara, Y. Murakumo, and M. Takahashi. “RET and neuroendocrine M. Ichihara, Y. Murakumo, and M. Takahashi. “RET and neuroendocrine tumors.” tumors.” Cancer LettersCancer Letters 204 (2004): 197—211. 204 (2004): 197—211.

S. Manie, M. Santoro, A. Fusco and M. Billaud. “The RET receptor: function in S. Manie, M. Santoro, A. Fusco and M. Billaud. “The RET receptor: function in development and dysfunction in congenital malformation.” development and dysfunction in congenital malformation.” TRENDS in GeneticsTRENDS in Genetics 17 (2001): 580—589.17 (2001): 580—589.

M. Tang, D. Worley, M. Sanicola, and G. Dressler. “The RET-Glial Cell-derived M. Tang, D. Worley, M. Sanicola, and G. Dressler. “The RET-Glial Cell-derived Neurotrophic Factor (GDNF) Pathway Stimulates Migration and Chemoattraction Neurotrophic Factor (GDNF) Pathway Stimulates Migration and Chemoattraction of Epithelial Cells.” of Epithelial Cells.” The Journal of Cell BiologyThe Journal of Cell Biology 142 (1998): 1337—1345. 142 (1998): 1337—1345.

M. Vidal, S. Wells, R. Anderson, and R. Cagan. “ZD6474 Suppresses Oncogenic M. Vidal, S. Wells, R. Anderson, and R. Cagan. “ZD6474 Suppresses Oncogenic RET Isoforms in a Drosophila Model for Type 2 Multiple Endocrine Neoplasia RET Isoforms in a Drosophila Model for Type 2 Multiple Endocrine Neoplasia Syndromes and Papillary Thyroid Carcinoma.” Syndromes and Papillary Thyroid Carcinoma.” Cancer ResearchCancer Research 65 (2005): 65 (2005): 3538—3541.3538—3541.

(Basic information about different types of cancer was searched for at (Basic information about different types of cancer was searched for at www.emedicine.com)www.emedicine.com)

ret and men2

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