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Receptor protein tyrosine phosphatase-receptor tyrosine kinase substrate screen identifies EphA2 as a target for LAR

Hojin Lee1, Anton M Bennett

  • 1Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.

Molecular and Cellular Biology
|January 30, 2013
PubMed

Insights

Receptor protein tyrosine phosphatases (RPTPs) regulate receptor tyrosine kinase (RTK) dephosphorylation, with each RPTP uniquely impacting RTK signaling. LAR was identified as a phosphatase for EphA2, modulating cell migration.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Receptor tyrosine kinases (RTKs) are crucial in cell signaling, existing in a balance of phosphorylation and dephosphorylation.
  • While RTK phosphorylation is well-understood, the mechanisms of RTK dephosphorylation, particularly by receptor protein tyrosine phosphatases (RPTPs), remain less clear.

Purpose of the Study:

  • To identify RPTPs involved in RTK dephosphorylation using a genome-wide siRNA screen.
  • To elucidate the specific roles of RPTPs in regulating RTK activity and downstream signaling pathways.

Main Methods:

  • Genome-wide small interfering RNA (siRNA) screen to identify RPTPs acting as RTK phosphatases.
  • Analysis of RPTP-induced changes in tyrosyl phosphorylation patterns across 42 RTKs.
  • Biochemical validation of LAR as an EphA2 phosphatase.

Main Results:

  • Each RPTP exhibited a distinct dephosphorylation "fingerprint" across a panel of 42 RTKs.
  • EphA2 was identified as a novel substrate for the RPTP LAR.
  • LAR specifically dephosphorylated EphA2 at phosphotyrosine 930, disrupting Nck1 binding and reducing EphA2-mediated cell migration.

Conclusions:

  • RPTPs exert unique regulatory control over RTK tyrosyl dephosphorylation, indicating a complex interplay between these two signaling families.
  • LAR-mediated, site-specific dephosphorylation of EphA2 is a key mechanism for modulating cell migration.

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