PTP1B regulates cortactin tyrosine phosphorylation by targeting Tyr446.
The emergence of protein-tyrosine phosphatase 1B (PTP1B) as a potential drug target for treatment of diabetes, obesity, and cancer underlies the importance of understanding its full range of cellular functions. Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr(446), the regulation and function of which have not previously been characterized. We show that phosphorylation of cortactin Tyr(446) is induced by hyperosmolarity and potentiates apoptotic signaling during prolonged hyperosmotic stress. This study advances the importance of Tyr(446) in the regulation of cortactin and provides a potential mechanism to explain the effects of PTP1B on processes including cell adhesion, migration, and tumorigenesis.
Stuible
Matthew
M
McGill Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Dubé
Nadia
N
Tremblay
Michel L
ML
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D019556:COS Cells; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002522:Chlorocebus aethiops; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin; D014443:Tyrosine; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1