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NDR2 acts as the upstream kinase of ARK5 during insulin-like growth factor-1 signaling

Atsushi Suzuki1, Tsutomu Ogura, Hiroyasu Esumi

  • 1Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaiji, Okazaki, Aichi 444-8585, Japan.

The Journal of Biological Chemistry
|February 21, 2006
PubMed

Insights

Serine/threonine protein kinase NDR2 phosphorylates and activates ARK5, a key factor in tumor progression. This interaction, crucial in insulin-like growth factor (IGF)-1 signaling, promotes colorectal cancer cell survival and invasion.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Signal Transduction

Background:

  • ARK5 is a known factor in tumor progression, activated by AKT phosphorylation.
  • Full activation of ARK5 requires phosphorylation at its active T loop.
  • The precise upstream activators of ARK5 in specific signaling pathways remain an area of investigation.

Purpose of the Study:

  • To identify the upstream kinase responsible for ARK5 activation during insulin-like growth factor (IGF)-1 signaling.
  • To elucidate the mechanism by which this kinase activates ARK5 and contributes to cancer cell behaviors.
  • To investigate the regulatory mechanisms controlling the identified upstream kinase.

Main Methods:

  • Kinase assays to determine direct phosphorylation of ARK5 by candidate kinases.
  • Cell-based assays using colorectal cancer cell lines to assess cell survival and invasion.
  • Site-directed mutagenesis to investigate the role of specific phosphorylation residues in kinase activation and function.
  • Co-immunoprecipitation to study protein-protein interactions.

Main Results:

  • Serine/threonine protein kinase NDR2 was identified as a direct upstream kinase that phosphorylates and activates ARK5.
  • NDR2 phosphorylates ARK5 at threonine 211 on the active T loop, promoting colorectal cancer cell survival and invasion.
  • NDR2 activation requires phosphorylation at threonine 75, serine 282, and threonine 442, with serine 282 phosphorylation being critical.
  • NDR2 interacts with S100B in a calcium- and phospholipase C-gamma-dependent manner.
  • PDK-1 plays a role in NDR2 activation, particularly in phosphorylating threonine 442.

Conclusions:

  • NDR2 is a crucial upstream kinase that activates ARK5 during IGF-1 signaling.
  • The NDR2-ARK5 axis plays a significant role in promoting colorectal cancer cell survival and invasion.
  • Understanding the regulation of NDR2 and its activation of ARK5 provides potential therapeutic targets for cancer progression.

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