MADR2 maps to 18q21 and encodes a TGFbeta-regulated MAD-related protein that is functionally mutated in colorectal carcinoma.
The MAD-related (MADR) family of proteins are essential components in the signaling pathways of serine/threonine kinase receptors for the transforming growth factor beta (TGFbeta) superfamily. We demonstrate that MADR2 is specifically regulated by TGFbeta and not bone morphogenetic proteins. The gene for MADR2 was found to reside on chromosome 18q21, near DPC4, another MADR protein implicated in pancreatic cancer. Mutational analysis of MADR2 in sporadic tumors identified four missense mutations in colorectal carcinomas, two of which display a loss of heterozygosity. Biochemical and functional analysis of three of these demonstrates that the mutations are inactivating. These findings suggest that MADR2 is a tumor suppressor and that mutations acquired in colorectal carcinomas may function to disrupt TGFbeta signaling.
Eppert
K
K
Division of Gastroenterology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Scherer
S W
SW
Ozcelik
H
H
Pirone
R
R
Hoodless
P
P
Kim
H
H
Tsui
L C
LC
Bapat
B
B
Gallinger
S
S
Andrulis
I L
IL
Thomsen
G H
GH
Wrana
J L
JL
Attisano
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002887:Chromosomes, Human, Pair 18; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000737:chemistry; D010750:Phosphoproteins / Q000235:genetics*; D010766:Phosphorylation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051899:Smad2 Protein; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D016212:Transforming Growth Factor beta / Q000502:physiology*; D029867:Xenopus Proteins; D014982:Xenopus laevis
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D015345:Oligonucleotide Probes; D010750:Phosphoproteins; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins