Girdin is a component of the lateral polarity protein network restricting cell dissemination

Abstract

27Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the 28 functional interactions within the polarity protein network. Here we show that Drosophila Girdin 29 and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by 30 inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with 31 overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination 32 from GIRDIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the 33 cohesion of multicellular epithelial structures. Consistent with these observations, alteration 34 of GIRDIN expression is associated with a poor overall survival in subtypes of breast and lung 35 cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization 36 from flies to humans. Our data also indicate that GIRDIN has the potential to impair the 37 progression of epithelial cancers by preserving cell polarity and restricting cell dissemination. 38 39

A long isoform of GIV/Girdin contains a PDZ-binding module that regulates localization and G-protein binding

“…The well-differentiated CRC cell line Caco-2 is known to form well-defined junctions, was recently shown to have morphogenesis defects upon GIV depletion ( 50 ) and confirmed to express GIV-L ( Fig. 2 C ).…”

“…While most of the work to date support a pro-oncogenic and prometastatic role for GIV ( 19 , 30 , 47 , 48 , 49 ), a few have revealed a tumor suppressive function for GIV ( 50 , 51 ). The pro-oncogenic roles have been demonstrated in stromal cells (Cos7, Vero) or epithelial cells with no ( e.g.…”

“…, MDA MB231) or weak junctions (HeLa), whereas tumor suppressive effects were shown in cells with junctions (MDCK, Caco-2, etc.) ( 13 , 50 ).…”

“…2 C ). Therefore, we proceeded with the use of the same GIV-depleted (by shRNA) Caco-2 cell line as a model system for a series of phenotypic studies ( 50 ). First, we found that loss of GIV was associated also with a loss of contact-dependent growth arrest, as determined by growth of cells in patches of “piled-up” cells in monolayers (circle; Fig.…”

“…Based on these observations, GIV has been generally believed to serve primarily as an oncogene that fuels cancer initiation and progression. However, this belief has recently been challenged by others who have suggested a tumor-suppressive role for GIV ( 50 ), although the molecular mechanism for such contrasting roles for the same protein was not revealed. By showing here that GIV-L maintains epithelial homeostatic properties ( e.g.…”