Protocadherin LKC, a new candidate for a tumor suppressor of colon and liver cancers, its association with contact inhibition of cell proliferation.
Protocadherins are a major subfamily of the cadherin superfamily, but little is known about their functions and intracellular signal transduction. We cloned a novel human protocadherin gene, containing seven EC domains, and identified functional aspects of this gene. The gene was predominantly expressed in liver, kidney and colon tissues, and was thus designated Protocadherin LKC. The expression of Protocadherin LKC is markedly reduced in cancers arising from these tissues at both transcriptional and protein levels. To investigate the effects of Protocadherin LKC expression in colon cancer, we introduced the gene into colon cancer cell line HCT116, which does not express this gene. Significantly, Protocadherin LKC expression induced contact inhibition of cell proliferation although it did not affect growth rate. When grown to post-confluence in monolayer cells cultures, Protocadherin LKC-expressing HCT116 no longer formed multiple cell layers and showed the typical paving stone morphology of normal epithelial cells. Furthermore, expression of Protocadherin LKC suppressed tumor formation of HCT116 cells in a nude mouse model. In addition, we identified a protein, hMAST205 (microtubule-associated serine/threonine kinase-205 kDa), which interacted with Protocadherin LKC; the interaction occurring between the PDZ domain of hMAST205 and C-terminal tail of Protocadherin LKC. Our results suggest that Protocadherin LKC, which directly binds PDZ protein, is a molecular switch for contact inhibition of epithelial cells in the liver, kidney and colon tissues.
Okazaki
Noriko
N
Helix Research Institute, 1532-3 Yana, Kisarazu-city, Chiba 292-0812, Japan.
Takahashi
Naomi
N
Kojima
Shin-Ichi
S
Masuho
Yasuhiko
Y
Koga
Hisashi
H
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division; D003001:Cloning, Molecular; D003106:Colon / Q000166:cytology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000032:analysis; D015536:Down-Regulation; D015870:Gene Expression; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000166:cytology; D008099:Liver / Q000166:cytology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae; D014407:Tumor Cells, Cultured
D000199:Actins; C464586:CDHR2 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D017931:DNA Primers; D018076:DNA, Complementary; D008869:Microtubule-Associated Proteins; C084505:Mtssk protein, mouse; D012333:RNA, Messenger; D017346:Protein Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase