The following article refers to contact inhibition of cell division in epithelial cells, specifically MDCK cells: Collective and single cell behavior in epithelial contact inhibition.
In their review of the literature, there are a number of possible signalling pathways implicated in contact inhibition of cell division. These pathways are outlined in the following quotes:
It is widely accepted that contact inhibition requires establishment of E-cadherin-mediated cell-cell contacts and subsequent maturation of the adherens junctions (AJs) that link E-cadherin and F-actin in a synapse-like complex involving numerous other proteins
One possible pathway involves β-catenin, a mediator of Wnt signalling, that, in addition to its function as a transcriptional cofactor, is associated with the AJs at the cell surface
A contact inhibition role has been reported for NF2/Merlin, a tumor suppressor gene that encodes a membrane-cytoskeletal scaffolding protein, which most likely acts via the Hippo kinase pathway, controlling nuclear localization of the transcriptional activator YAP—itself a known regulator of cell proliferation.
Contact inhibition is known to involve the MAPK pathway, which, in turn, promotes cell cycle entry by regulating the expression of cyclinD1. Also implicated are Nectins—a family of cell adhesion molecules that are involved, together with integrins and other proteins, in the regulation of cell motility and proliferation. Yet, this accumulated knowledge falls far short of a comprehensive picture of contact inhibition.
In the article, the findings were as follows:
Our findings show that contact between cells is not sufficient for inhibition of mitosis in MDCK cells. Instead, inhibition of cell proliferation is a consequence of mechanical constraint that causes successive cell divisions to reduce cell area.
Where, in the discussion, they note the following:
Our measurements also suggest that inhibition of cell division is a distinct single cell state rather than a global state induced by cell-cell signalling across the layer, as illustrated in Fig. 4E. In fact, confluent MDCK cell cultures with an average cell density corresponding to the morphological transition are often sufficiently heterogeneous in local cell density that highly motile cells and completely arrested cells coexist in the same colony. Thus contact inhibition is a local phenomenon...
Published later, the article Spatial constraints control cell proliferation in tissues showed that reducing the amount of space in a tissue prevented entry into S-phase. Actually stretching the tissue quickly reactivated the cell cycle, and compression leads quickly to arrest. More so, they found that cells had no memory of past constraint, and were able to suggest a model of growth in relation to the spatial constraint.
I'm editing my question because the way I posted it initially, to me, was unanswerable. Being said, I suspect that at this point cell volume and extracellular contacts are synergistic. This is probably going to need two separate questions, but:
1) How does the mitotic entry machinery roughly respond to cell volume? I'm currently reading into Cdc25/Wee1 regulation in addition to some stuff about internal fluidics that are influenced by water, ion channels, etc. but I still don't fully understand.
2) What's a relatively straightforward downstream pathway (core elements), starting at the adherens junctions, that illustrates how cell-cell signalling gets the STOP signal to the mitotic entry machinery (based on what we know)? This might require some much more in-depth knowledge about the field, however, but articles with some good figures are appreciated, too.