RET

1
RET

• Multiple Endocrine Neoplasia Type 2 (MEN2)

Brooke Martin 3/20/08
2
History of RET

• Discovered in 1985 by the transfection of NIH3T3
  cells with DNA from T cell lymphoma cells
• RET stands for
• rearranged during transfection
• Can have either loss of function or gain of
  function mutations

3
RET Properties

• Transmembrane protein and RTK
• Mainly found in precursors of the urogenital
  system and neural crest
• Has 3 isoforms
• short (RET9), middle(RET43), and long (RET51)
• Homodimer
• Also pairs with GFR (growth factor receptor)a 1,
  2, 3, and 4
• Ligands
• GDNF (glial-derived neurotrophic factor),
  neurturin (NTN), persephin (PSP), and artemin

4
GDNF Family with Receptors
SIGMA-ALDRICH
5
RET Properties Continued

• Gene found on long arm of chromosome 10 at 11.2
• Gene has 21 exons
• Cadherin part must bind with Ca2 in order for
  RET to work
• 5 phosphotyrosine residues
• 2 more in long isoform

6
Protein Structures of RET
Unphosphorylated
Phosphorylated
J. Biol. Chem. v281, p.33577-33587
7
What Does RET Do Normally?

• Helps with kidney development and enteric nervous
  system
• Also implicated in cell differentiation and
  apoptosis

8
Knockout Mice

• Knockouts had no neurons in the gut, superior
  cervical ganglia, no kidneys at all or malformed
  and malfunctioning
• RET null mutation die shortly after birth
• No endocrine organs affected in MEN 2
• Heterozygotes have no apparent defects

9
MEN 2-multiple endocrine neoplasia type 2

• Inherited form of cancer and very rare
• First to be discovered in 1993 that MEN 2 was
  caused by germline mutations
• Three subtypes
• MEN 2A and MEN 2B
• Familial medullary thyroid carcinoma (FMTC)
• Autosomal dominant
• RET constitutively active
• Endocrine glands affected
• Adrenal, parathyroid, and thyroid
• Gain of function mutations

10
MEN 2A
11
MEN 2B
12
FMTC

• Have the same mutations as 2A in extracellular
  domain but also can be in TK domain at 768, 790,
  791,(exon 13) 804, 844,(exon 14) or 891
  (exon15)
• Have mild C cell disease
• Low transforming activity can predispose to FMTC
  rather than MEN 2A

13
Treatment and Testing

• Thyroidectomy
• Before age 6 or 6-12 depending on mutation
• If MEN 2B, needed before a year old
• Have to take thyroid for the rest of life
• Chemotherapy not effective
• Microarray (best)
• Direct sequencing or single-strand conformational
  polymorphism
• Drugs being tested to disrupt RET kinase activity
• Needs a higher concentration though

14
Questions?