Protein-tyrosine phosphatase PCP-2 inhibits beta-catenin signaling and increases E-cadherin-dependent cell adhesion.
beta-Catenin is a key molecule involved in both cell adhesion and Wnt signaling pathway. However, the exact relationship between these two roles has not been clearly elucidated. Tyrosine phosphorylation of beta-catenin was shown to decrease its binding to E-cadherin, leading to decreased cell adhesion and increased beta-catenin signaling. We have previously shown that receptor-like protein-tyrosine phosphatase PCP-2 localizes to the adherens junctions and directly binds and dephosphorylates beta-catenin, suggesting that PCP-2 might regulate the balance between signaling and adhesive beta-catenin. Here we demonstrate that PCP-2 can inhibit both the wild-type and constitutively active forms of beta-catenin in activating target genes such as c-myc. The phosphatase activity of PCP-2 is required for this effect since loss of catalytic activity attenuates its inhibitory effect on beta-catenin activation. Expression of PCP-2 in SW480 colon cancer cells can lead to stabilization of cytosolic pools of beta-catenin perhaps, by virtue of their physical interaction. PCP-2 expression also leads to increased membrane-bound E-cadherin and greater stabilization of adherens junctions by dephosphorylation of beta-catenin, which could further sequester cytosolic beta-catenin and thus inhibit beta-catenin mediated nuclear signaling. Furthermore, SW480 cells stably expressing PCP-2 have a reduced ability to proliferate and migrate. Thus, PCP-2 may play an important role in the maintenance of epithelial integrity, and a loss of its regulatory function may be an alternative mechanism for activating beta-catenin signaling.
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438.
He-Xin
HX
Yan
Wen
W
Yang
Rui
R
Zhang
Lei
L
Chen
Liang
L
Tang
Bo
B
Zhai
Shu-Qin
SQ
Liu
Hui-Fang
HF
Cao
Xiao-Bo
XB
Man
Hong-Ping
HP
Wu
Meng-Chao
MC
Wu
Hong-Yang
HY
Wang
D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D003593:Cytoplasm / Q000378:metabolism; D016259:Genes, myc; D006801:Humans; D008566:Membranes / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
C495270:CTNNB1 protein, human; D015820:Cadherins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D051176:beta Catenin; C516868:PTPRU protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2