Gas6 induces growth, beta-catenin stabilization, and T-cell factor transcriptional activation in contact-inhibited C57 mammary cells.
Gas6 is a growth factor related to protein S that was identified as the ligand for the Axl receptor tyrosine kinase (RTK) family. In this study, we show that Gas6 induces a growth response in a cultured mammalian mammary cell line, C57MG. The presence of Gas6 in the medium induces growth after confluence and similarly causes cell cycle reentry of density-inhibited C57MG cells. We show that Axl RTK but not Rse is efficiently activated by Gas6 in density-inhibited C57MG cells. We have analyzed the signaling required for the Gas6 proliferative effect and found a requirement for PI3K-, S6K-, and Ras-activated pathways. We also demonstrate that Gas6 activates Akt and concomitantly inhibits GSK3 activity in a wortmannin-dependent manner. Interestingly, Gas6 induces up-regulation of cytosolic beta-catenin, while membrane-associated beta-catenin remains unaffected. Stabilization of beta-catenin in C57MG cells is correlated with activation of a T-cell factor (TCF)-responsive transcriptional element. We thus provide evidence that Gas6 is mitogenic and induces beta-catenin proto-oncogene stabilization and subsequent TCF/Lef transcriptional activation in a mammary system. These results suggest that Gas6-Axl interaction, through stabilization of beta-catenin, may have a role in mammary development and/or be involved in the progression of mammary tumors.
Goruppi
S
S
LNCIB (Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie), 34012 Trieste, Italy.
Chiaruttini
C
C
Ruaro
M E
ME
Varnum
B
B
Schneider
C
C
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003260:Contact Inhibition; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D051176:beta Catenin; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D038362:Glycogen Synthase Kinase 3; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011506:Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; C000715470:MAS1 protein, human; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; C553059:Tcf7l2 protein, rat