RET Proto- Oncogene in The Development of Thyroid Cancer:

Multiple Endocrine Neoplasia Type 2

Courtney BrooksCourtney Brooks

Overview

MEN Type 2MEN Type 2 RET Gene-Role in Normal DevelopmentRET Gene-Role in Normal Development Normal RET Signaling PathwayNormal RET Signaling Pathway Mutations Responsible for MEN Type 2Mutations Responsible for MEN Type 2 Mutant RET Signaling PathwayMutant RET Signaling Pathway Diagnosis and Treatment for the CancerDiagnosis and Treatment for the Cancer

Multiple Endocrine Neoplasia Type 2

Thyroid CancerThyroid Cancer Germ line point mutations in Germ line point mutations in

RET gene.RET gene. Cause over activation of RET Cause over activation of RET Triggers Triggers proliferation in proliferation in

endocrine cells. endocrine cells.

3 Forms of MEN Type 2

MEN Type 2aMEN Type 2a

MEN Type 2bMEN Type 2b

FMTCFMTC

RET

Gene on chromosome 10 q 11.2Gene on chromosome 10 q 11.2

Encodes a receptor tyrosine kinase Encodes a receptor tyrosine kinase

Required for maturation of nervous system Required for maturation of nervous system and kidney morphogenesisand kidney morphogenesis

RET: Role in Normal Development

RET deficient mice :RET deficient mice :

Die shortly after birthDie shortly after birth

Lack the Enteric Nervous SystemLack the Enteric Nervous System

Display Renal Agenesis (no Kidney)Display Renal Agenesis (no Kidney)

Have Fewer Thyroid C CellsHave Fewer Thyroid C Cells

Components of the RET Signaling Pathway

Co-receptors:Co-receptors:

GFR GFR 1, 1, 2, 3, & 42, 3, & 4

Growth Factor Ligands:Growth Factor Ligands:

GDNF, NRTN, ARTN, PSPNGDNF, NRTN, ARTN, PSPN

GDNFGFR 1 1

P

P

RET

RAS-RAF Pathway PI3 Kinase Pathway

Cell Membrane

Cys

Cys

Cys

Cys

Extracellular Domain

Intracellular Domain

RET Proto-Oncogene in MEN Type 2

Germline point mutations of RET are Germline point mutations of RET are responsible for all Forms of MEN Type responsible for all Forms of MEN Type MEN 2 MEN 2

The mutations affect either the extracellular The mutations affect either the extracellular or the intracellular tyrosine kinase domain or the intracellular tyrosine kinase domain of RET receptor.of RET receptor.

RET Gene Showing Mutations For

MEN Type 2

The Effects of Mutations on RET Function

Ligand independent dimerization, Ligand independent dimerization, activation, and transformation. activation, and transformation.

Constitutive Phosphorylation of Constitutive Phosphorylation of intracellular proteins. intracellular proteins.

Overactive Signaling Overactive Signaling

P

P

RET

Cell Membrane

Cys

Cys

Arg

Cys

P

P

Over Active Signalling to CellsUncontrolled

Cell Proliferation

Extracellular Domain

Intracellular Domain

GFR 1 1

Diagnosis and Management of MEN Type 2

Genetic Screening for Genetic Screening for RET mutationsRET mutations

ThyrodectomyThyrodectomy New Therapeutic New Therapeutic

Strategies : Inhibitors Strategies : Inhibitors specific for RET specific for RET oncoproteinsoncoproteins

Sources

Albert, L. Carniti, C. RET and NTRK1. 2003. Proto-Oncogenes in Albert, L. Carniti, C. RET and NTRK1. 2003. Proto-Oncogenes in Human Diseases. Journal of Cellular Physiology. 195: 168-Human Diseases. Journal of Cellular Physiology. 195: 168-

186186 Manie, S. Santoro, M. 2001. The RET receptor: function in Manie, S. Santoro, M. 2001. The RET receptor: function in

development and dysfunction in congenital malformation. development and dysfunction in congenital malformation. Trends Trends in Genetics. 17 (10): 580-589 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 Borello, MG, Mercalli E. 1995. RET activation by germline MEN

2A, and MEN 2 B mutations. Oncogene 11:2419-24272A, and MEN 2 B mutations. Oncogene 11:2419-2427 Mulligan LM, et al. Specific mutations of the RET proto-oncogene are Mulligan LM, et al. Specific mutations of the RET proto-oncogene are

related to MEN 2A and FMTC. Nat Genet. 1994; 6(1):70-4related to MEN 2A and FMTC. Nat Genet. 1994; 6(1):70-4