ret proto- oncogene in the development of thyroid cancer: multiple endocrine neoplasia type 2
DESCRIPTION
RET Proto- Oncogene in The Development of Thyroid Cancer: Multiple Endocrine Neoplasia Type 2. Courtney Brooks. Overview. MEN Type 2 RET Gene-Role in Normal Development Normal RET Signaling Pathway Mutations Responsible for MEN Type 2 Mutant RET Signaling Pathway - PowerPoint PPT PresentationTRANSCRIPT
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