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RET and MEN2
This presentation brought to you
by Meredith Stewart
The Disease:
MEN = Multiple endocrine neoplasia
MEN 2 Cancers
Familial Medullary Thyroid
Carcinoma
 MEN 2A
 MEN 2B

Medullary
thyroid
carcinoma (C cells)
Pheochromocytoma
(adrenal tumors)
Parathyroid hyperplasia
MEN 2 Cancer, con’t:
Autosomal dominant inheritance
 Nearly 100 % penetrance
 1 case out of 30,000 – 50,000 people


Treatment options:
– Remove the thyroid
– Inhibit malfunctioning protein’s action
RET = The Bad Guy
(Rearranged during Transfection)
Proto-oncogene
 Receptor tyrosine
kinase

RET = The Bad Guy
(Rearranged during Transfection)
Proto-oncogene
 Receptor tyrosine
kinase
 One of pathways is in
fact Ras  MAPK

Many paths to follow…
Many paths to follow…
A less detailed view
Coreceptor = GFRα
family
 Ligand = GFL family
 Cysteine region
autophosphorylates
when bound by ligand
 Phosphorylates other
substrates

Normal RET Function?
“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?
Knockout Mice
Homozygous knockouts
have no kidneys!!!
Normal RET Function?
Knockout Mice
Homozygous knockouts
have no kidneys!!!
Normal RET Function?
“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)
What goes wrong in cancer?

Proto-oncogene 
constituvely active
What goes wrong in cancer?

Proto-oncogene 
constituvely active
FMTC: cysteine mutation
(extracellular domain)
 MEN 2A: cysteine mutation
at codon 634

What goes wrong in cancer?

Proto-oncogene 
constituvely active
FMTC: cysteine mutation
(extracellular domain)
 MEN 2A: cysteine mutation
at codon 634
 MEN 2B: kinase mutation at
codon 918

When RET goes bad…
Loss of function RET leads to Hirschsprung
disease (recessive)
 Overactive RET can also lead to papillary
thryoid cancer

BUT LOOK!!!
Normal RET
Too much RET
Too much RET
+ zd6474
Washington University School of Medicine performed this experiment:
The third eye shown was treated during
development with kinase inhibitor zd6474 and
mostly rescued
Works Referenced








L. Alberti, C. Carniti, C. Miranda, E. Roccatto, and M. Pierotti. “RET and NRTK1 ProtoOncogenes 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.
Hofstra, Robert M.W. “The RET gene and its associated diseases.” Diss. Department of
Medical Genetics, University of Groningen. Netherlands: 1995. 15—19. Accessed at
http://dissertations.ub.rug.nl/FILES/faculties/medicine/1995/r.m.w.hofstra/thesis.pdf
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.
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.
(Basic information about different types of cancer was searched for at
www.emedicine.com)