Receptor protein tyrosine phosphatase-receptor tyrosine kinase substrate screen identifies EphA2 as a target for LAR in cell migration.
Receptor tyrosine kinases (RTKs) exist in equilibrium between tyrosyl-phosphorylated and dephosphorylated states. Despite a detailed understanding of how RTKs become tyrosyl phosphorylated, much less is known about RTK tyrosyl dephosphorylation. Receptor protein tyrosine phosphatases (RPTPs) can play essential roles in the dephosphorylation of RTKs. However, a complete understanding of the involvement of the RPTP subfamily in RTK tyrosyl dephosphorylation has not been established. In this study, we have employed a small interfering RNA (siRNA) screen to identify RPTPs in the human genome that serve as RTK phosphatases. We observed that each RPTP induced a unique fingerprint of tyrosyl phosphorylation among 42 RTKs. We identified EphA2 as a novel LAR substrate. LAR dephosphorylated EphA2 at phosphotyrosyl 930, uncoupling Nck1 from EphA2 and thereby attenuating EphA2-mediated cell migration. These results demonstrate that each RPTP exerts a unique regulatory fingerprint of RTK tyrosyl dephosphorylation and suggest a complex signaling interplay between RTKs and RPTPs. Furthermore, we observed that LAR modulates cell migration through EphA2 site-specific dephosphorylation.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
Hojin
H
Lee
Anton M
AM
Bennett
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002522:Chlorocebus aethiops; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D036104:Receptor, EphA2 / Q000378:metabolism*; D054557:Receptor-Like Protein Tyrosine Phosphatases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C078332:Nck protein; D015513:Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D036104:Receptor, EphA2; D054557:Receptor-Like Protein Tyrosine Phosphatases