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Integrin-binding protein nischarin interacts with tumor suppressor liver kinase B1 (LKB1) to regulate cell migration

Prachi Jain1, Somesh Baranwal, Shengli Dong

  • 1Department of Biochemistry and Molecular Biology, School of Medicine, Louisiana State University Health Science Center, New Orleans, Louisiana 70112, USA.

The Journal of Biological Chemistry
|April 11, 2013
PubMed

Insights

The tumor suppressor Nischarin interacts with LKB1 to inhibit breast cancer progression. Loss of both proteins enhances cell migration, tumor growth, and lung metastasis formation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Biallelic inactivation of LKB1 (serine/threonine kinase) occurs in 30% of lung adenocarcinomas.
  • LKB1 is known to inhibit breast tumor growth.
  • Nischarin is a tumor suppressor with an uncharacterized role in cancer progression.

Purpose of the Study:

  • To identify novel binding partners of LKB1.
  • To investigate the functional interaction between Nischarin and LKB1 in breast cancer.
  • To elucidate the molecular mechanisms by which Nischarin and LKB1 regulate cell migration and tumor progression.

Main Methods:

  • Protein interaction mapping using N-terminal mapping.
  • Cell migration assays (time-lapse microscopy, Transwell migration).
  • In vivo tumor growth and metastasis studies.
  • Flow cytometry for cell cycle analysis.
  • Western blotting for protein phosphorylation and expression analysis.

Main Results:

  • Nischarin directly binds to LKB1 (amino acids 44-436).
  • Absence of Nischarin and LKB1 significantly enhances MDA-MB-231 cell migration and invasion.
  • Loss of Nischarin and LKB1 increases tumor growth, S-phase population, and cyclin D1 levels in vivo.
  • Co-absence of Nischarin and LKB1 dramatically increases lung metastasis formation.
  • The combined absence of Nischarin and LKB1 elevates PAK1 and LIMK1 phosphorylation, suggesting dysregulation of the PAK-LIMK-Cofilin pathway.
  • These proteins together regulate cyclin D1/CDK4 pathways.

Conclusions:

  • This study demonstrates a novel functional interaction between the tumor suppressor Nischarin and LKB1.
  • Nischarin and LKB1 cooperate to inhibit breast cancer cell migration, invasion, tumor growth, and metastasis.
  • The mechanism involves the regulation of PAK-LIMK-Cofilin and cyclin D1/CDK4 pathways.
Keywords:
Breast CancerMigrationProtein PhosphorylationRho GTPasesTumor Metastases

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