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Updated: Jul 12, 2026

Development and Application of Rapamycin-regulated Tyrosine Phosphatases
06:56

Development and Application of Rapamycin-regulated Tyrosine Phosphatases

Published on: September 6, 2024

The tumor suppressor DAPK is reciprocally regulated by tyrosine kinase Src and phosphatase LAR

Won-Jing Wang1, Jean-Cheng Kuo, Wei Ku

  • 1Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.

Molecular Cell
|September 7, 2007
PubMed

Insights

Leukocyte common antigen-related tyrosine phosphatase (LAR) dephosphorylates Death-associated protein kinase (DAPK), enhancing its tumor-suppressing activity. Conversely, Src kinase inactivates DAPK, promoting cancer cell migration and invasion.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Death-associated protein kinase (DAPK) is a serine/threonine kinase with tumor suppressor functions, inhibiting cell adhesion/migration and promoting apoptosis.
  • The precise regulatory mechanisms governing DAPK activity remain largely unknown.

Purpose of the Study:

  • To elucidate the signaling pathways regulating DAPK activity.
  • To investigate the roles of leukocyte common antigen-related tyrosine phosphatase (LAR) and Src kinase in DAPK regulation.
  • To establish a link between DAPK regulation and tumor progression.

Main Methods:

  • Investigated the phosphorylation status of DAPK at Y491/492.
  • Utilized biochemical assays to assess DAPK activity, dephosphorylation by LAR, and phosphorylation by Src.
  • Examined the effects of EGF stimulation on Src, LAR, and DAPK activity in cancer cells.
  • Analyzed DAPK phosphorylation in human cancer tissues.

Main Results:

  • LAR tyrosine phosphatase dephosphorylates DAPK at pY491/492, stimulating its catalytic, proapoptotic, and antiadhesion/antimigration activities.
  • Src kinase phosphorylates DAPK at Y491/492, leading to its inactivation.
  • EGF stimulation activates Src and downregulates LAR, synergistically inactivating DAPK and promoting tumor cell migration.
  • DAPK Y491/492 hyperphosphorylation correlates with elevated Src activity in human cancers.

Conclusions:

  • LAR and Src act as key regulators of DAPK through reciprocal phosphorylation/dephosphorylation at Y491/492.
  • This DAPK-regulatory circuit involving LAR and Src plays a critical role in facilitating tumor cell migration, invasion, and overall cancer progression.

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