Continuous association of cadherin with beta-catenin requires the non-receptor tyrosine-kinase Fer.
The function of Type 1, classic cadherins depends on their association with the actin cytoskeleton, a connection mediated by alpha- and beta-catenin. The phosphorylation state of beta-catenin is crucial for its association with cadherin and thus the association of cadherin with the cytoskeleton. We now show that the phosphorylation of beta-catenin is regulated by the combined activities of the tyrosine kinase Fer and the tyrosine phosphatase PTP1B. Fer phosphorylates PTP1B at tyrosine 152, regulating its binding to cadherin and the continuous dephosphorylation of beta-catenin at tyrosine 654. Fer interacts with cadherin indirectly, through p120ctn. We have mapped the interaction domains of Fer and p120ctn and peptides corresponding to these sequences release Fer from p120ctn in vitro and in live cells, resulting in loss of cadherin-associated PTP1B, an increase in the pool of tyrosine phosphorylated beta-catenin and loss of cadherin adhesion function. The effect of the peptides is lost when a beta-catenin mutant with a substitution at tyrosine 654 is introduced into cells. Thus, Fer phosphorylates PTP1B at tyrosine 152 enabling it to bind to the cytoplasmic domain of cadherin, where it maintains beta-catenin in a dephosphorylated state. Cultured fibroblasts from mouse embryos targeted with a kinase-inactivating ferD743R mutation have lost cadherin-associated PTP1B and beta-catenin, as well as localization of cadherin and beta-catenin in areas of cell-cell contacts. Expression of wild-type Fer or culture in epidermal growth factor restores the cadherin complex and localization at cell-cell contacts.
Xu
Gang
G
Department of Biological Sciences, The University of Iowa, Iowa City 52242, USA.
Craig
Andrew W B
AW
Greer
Peter
P
Miller
Matthew
M
Anastasiadis
Panos Z
PZ
Lilien
Jack
J
Balsamo
Janne
J
D000818:Animals; D051943:Antennapedia Homeodomain Protein; D015153:Blotting, Western; D001921:Brain / Q000196:embryology; D015820:Cadherins / Q000378:metabolism*; D051177:Catenins; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D012160:Retina / Q000196:embryology; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D051176:beta Catenin; D000095002:Delta Catenin
D051943:Antennapedia Homeodomain Protein; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D010455:Peptides; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C502406:fat1 protein, mouse; C052602:proto-oncogene protein c-fes-fps; D014443:Tyrosine; D005982:Glutathione Transferase; D011505:Protein-Tyrosine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516609:Ptpn1 protein, mouse; D000095002:Delta Catenin; C000722349:Ctnnd1 protein, mouse