Regulation of insulin-like growth factor type I (IGF-I) receptor kinase activity by protein tyrosine phosphatase 1B (PTP-1B) and enhanced IGF-I-mediated suppression of apoptosis and motility in PTP-1B-deficient fibroblasts.
The insulin-like growth factor type I (IGF-I) receptor (IGF-IR), activated by its ligands IGF-I and IGF-II, can initiate several signal transduction pathways that mediate suppression of apoptosis, proliferation, differentiation, and transformation. Here we investigated the regulation of IGF-IR activation and function by protein tyrosine phosphatase 1B (PTP-1B). Coexpression of PTP-1B with a beta-chain construct of the IGF-IR (betaWT) inhibited IGF-IR kinase activity in fission yeast Schizosaccharomyces pombe, in COS cells, and in IGF-IR-deficient fibroblasts. In both spontaneously immortalized and simian virus 40 T antigen-transformed embryonic fibroblast cell lines derived from PTP-1B knockout mice, IGF-I induced higher levels of IGF-IR autophosphorylation and kinase activity than were induced in PTP-1B-expressing control cells. PTP-1B-deficient cells exhibited enhanced IGF-I-mediated protection from apoptosis in response to serum withdrawal or etoposide killing, as well as enhanced plating efficiency and IGF-I-mediated motility. Reexpression of PTP-1B in spontaneously immortalized fibroblasts resulted in decreased IGF-IR and AKT activation, as well as decreased protection from apoptosis and decreased motility. These findings demonstrate that PTP-1B can regulate IGF-IR kinase activity and function and that loss of PTP-1B can enhance IGF-I-mediated cell survival, growth, and motility in transformed cells.
Buckley
Deirdre A
DA
Cell Biology Laboratory, Department of Biochemistry and Bioscience Research Institute, National University of Ireland, Cork, Ireland.
Cheng
Alan
A
Kiely
Patrick A
PA
Tremblay
Michel L
ML
O'Connor
Rosemary
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D003001:Cloning, Molecular; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017353:Gene Deletion; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021122:Protein Subunits; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors; D014945:Wound Healing
D016895:Culture Media, Serum-Free; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D021122:Protein Subunits; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D017526:Receptor, IGF Type 1; C516609:Ptpn1 protein, mouse