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PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth

Guennadi Kozlov1, Yosuke Funato2, Yu Seby Chen1

  • 1Department of Biochemistry and Centre de Recherche en Biologie Structurale, McGill University, Montreal, Quebec, Canada.

The Journal of Biological Chemistry
|June 24, 2020
PubMed

Insights

Phosphatases of regenerating liver (PRLs) do not require catalytic activity to promote cancer metastasis. Instead, PRL3 inhibits CNNM4 by binding, a mechanism crucial for tumor growth.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Phosphatases of regenerating liver (PRLs) are established cancer markers that promote tumor progression.
  • The specific physiological target and function of PRL phosphatase activity have remained elusive for two decades.

Purpose of the Study:

  • To investigate the role of PRL3 catalytic activity in cancer metastasis.
  • To identify the direct target of PRL3 and elucidate its mechanism of action in tumor growth.

Main Methods:

  • Utilized a mouse model of metastasis to assess the requirement of PRL3 catalytic activity.
  • Employed mutant PRL3 proteins to differentiate between CNNM-binding and phosphatase activity functions.
  • Analyzed PRL cysteine phosphorylation levels under varying conditions and in different tissues.

Main Results:

  • PRL3 catalytic activity was found to be dispensable for metastasis in a mouse model.
  • PRL3 directly binds and inhibits CNNM4, a magnesium transport-associated membrane protein.
  • CNNM4 binding, rather than phosphatase activity, was sufficient to drive tumor metastasis, reclassifying PRLs as pseudophosphatases.

Conclusions:

  • PRL3 functions as a pseudophosphatase, with its inhibitory binding to CNNM4 being critical for promoting cancer metastasis.
  • The formation of a stable phosphocysteine on PRLs, which blocks CNNM binding, suggests a regulatory role for its phosphatase activity.
  • These findings necessitate a re-evaluation of PRL inhibitor design strategies for cancer therapy.
Keywords:
autophosphorylationcancercysteine phosphorylationdual-specificity phosphoprotein phosphatasemagnesiummetastasisphosphocysteineprotein phosphatasepseudoenzymepseudophosphatase

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