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

Cell adhesion plays essential roles in almost every aspect of metazoan biology. LINKIN (Human: ITFG1, Caenorhabditis elegans : lnkn-1 ) is a conserved transmembrane protein that has been identified to be necessary for tissue integrity during migration. In C. elegans , loss of lnkn-1 results in the detachment of the lead migratory cell from the rest of the developing male gonad. Previously, three interactors of ITFG1/ lnkn-1 – RUVBL1/ ruvb-1 , RUVBL2/ ruvb-2 , and alpha-tubulin – were identified by immunoprecipitation-mass spectrometry (IP-MS) analysis using human HEK293T cells and then validated in the nematode male gonad. The ITFG1-RUVBL1 interaction has since been independently validated in a breast cancer cell line model that also implicates the involvement of the pair in metastasis. Here, we showed that epitope-tagged ITFG1 localized to the cell surface of MDA-MB-231 breast cancer cells. Using IP-MS analysis, we identified a new list of potential interactors of ITFG1. Loss-of-function analysis of their C. elegans orthologs found that three of the interactors – ATP9A/ tat-5 , NME1/ ndk-1 , and ANAPC2/ apc-2 – displayed migratory detachment phenotypes similar to that of lnkn-1 . Taken together with the other genes whose reduction-of-function phenotype is similar to that of lnkn-1 (notably cohesion and condensin), suggests the involvement of membrane remodeling and chromosome biology in LINKIN-dependent cell adhesion and supports the hypothesis for a structural role of chromosomes in post-mitotic cells.