Activation of TrkA tyrosine kinase in embryonal carcinoma cells promotes cell compaction, independently of tyrosine phosphorylation of catenins.
Cadherins are transmembrane receptors whose extracellular domain mediates homophilic cell-cell interactions, while their cytoplasmic domain associates with a family of proteins known as catenins. Although the mechanisms that regulate the assembly and functional state of cadherin-catenin complexes are poorly understood, current evidence supports a role for protein tyrosine kinase activity in regulating cell adhesion and migration. Tyrosine phosphorylation of catenins is thought to mediate loss of intercellular adhesion promoted by activation of receptor tyrosine kinases in epithelial cells. Here, we show that activation of ectopically expressed TrkA, the tyrosine kinase receptor for nerve growth factor (NGF), stimulates embryonal carcinoma P19 cells to develop extensive intercellular contacts and to assemble into closely packed clusters. Thus, activation of receptor tyrosine kinases can differentially regulate adhesiveness by cell-type-specific mechanisms. Furthermore, activation of TrkA in P19 and epithelial MDCK cells induces tyrosine phosphorylation of p120(ctn) and of beta-catenin, irrespective of the elicited cellular response. The selective Src tyrosine kinase inhibitor PP2, however, suppresses NGF- or HGF-induced tyrosine phosphorylation of catenins in both P19 and MDCK cells without interfering with the acquisition of a compacted or scattered phenotype. These findings provide a cogent argument for considering that tyrosine phosphorylation of catenins is dispensable for their interaction with cadherins and, ultimately, for the modulation of cadherin-based cell adhesion by receptor tyrosine kinases.
Cozzolino
M
M
Istituto di Neurobiologia, Area di Ricerca Roma Tor Vergata-PBI and Istituto di Biologia Cellulare, CNR, Viale Marx 43, Italy.
Giovannone
B
B
Serafino
A
A
Knudsen
K
K
Levi
A
A
Alemà
S
S
Salvatore
A
A
D000595:Amino Acid Sequence; D000818:Animals; D018236:Carcinoma, Embryonal / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D020932:Nerve Growth Factor / Q000494:pharmacology; D010641:Phenotype; D010766:Phosphorylation; D020917:Receptor, trkA / Q000378:metabolism*; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D051176:beta Catenin
D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; D020932:Nerve Growth Factor; D020917:Receptor, trkA