LINKIN-associated proteins necessary for tissue integrity during collective cell migration

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Cell adhesion is fundamental to metazoan biology, with the conserved transmembrane protein LINKIN (ITFG1/lnkn-1) essential for tissue integrity during migration.
• Loss of function in C. elegans lnkn-1 causes migratory cell detachment, highlighting its role in tissue cohesion.
• Previous studies identified RUVBL1, RUVBL2, and alpha-tubulin as ITFG1/lnkn-1 interactors, with the ITFG1-RUVBL1 interaction implicated in breast cancer metastasis.

Approach:

• Epitope-tagged ITFG1 was localized to the cell surface of MDA-MB-231 breast cancer cells.
• Immunoprecipitation-mass spectrometry (IP-MS) was employed to identify novel ITFG1 interactors.
• Loss-of-function analysis of C. elegans orthologs of identified interactors was performed to assess their role in cell migration.

Key Points:

• ITFG1 localizes to the cell surface in breast cancer cells.
• IP-MS identified ATP9A/tat-5, NME1/ndk-1, and ANAPC2/apc-2 as novel potential interactors of ITFG1.
• Loss-of-function mutations in the C. elegans orthologs of these interactors phenocopied the lnkn-1 migratory detachment defect.

Conclusions:

• The findings suggest that ATP9A, NME1, and ANAPC2 are involved in LINKIN-dependent cell adhesion.
• These results, alongside known roles of cohesion and condensin, implicate membrane remodeling and chromosome biology in cell adhesion.
• The study supports a hypothesis for a structural role of chromosomes in post-mitotic cells, extending the function of LINKIN beyond simple adhesion.