Contact inhibition (of proliferation) redux
Section snippets
Phenomenology: No cell is an island
The concept of CIP was first coined in the 1960s to describe the tendency of tissue culture cells to stop or slow their proliferation as they grew to confluence. This is clearly demonstrated by growth curves that plateau as cultures become confluent accompanied by evidence of cell cycle arrest in G1 [5, 6]. (The earlier literature often described the process as contact inhibition of ‘growth’; however, as ‘growth’ more precisely refers to changes in cell size, we will use the term
Cell–cell adhesion receptors as initiators of CIP
Cell–cell adhesion molecules have long been attractive candidate receptors to initiate CIP: there is an elegant parsimony in having molecular mechanisms that mediate recognition and cell–cell cohesion also serve to regulate proliferation. The realization that these receptors can activate or modulate cell signaling [11] also opened the possibility that they may affect pathways that regulate cell proliferation. Of the several classes of such adhesion receptors that are known, much attention has
Cell–cell adhesion and the Hippo pathway
Over the past decade, the Hippo pathway has emerged as a major conserved growth-regulatory mechanism that can integrate many biological cues and signals to control organ size by regulating both cell proliferation and apoptosis. The molecular details of the pathway have been the subject of many excellent recent reviews (e.g. [25, 26]). For the purposes of our discussion, the Hippo pathway ultimately regulates the action of the transcriptional co-activator, Yes-associated protein (YAP)-1 (in
Contact-dependent inhibition of growth factor receptors
Studies that first recognized the phenomenon of CIP appreciated that as cultured cells reach confluence, the response to serum growth factors is progressively inhibited despite the continuous replenishment of growth factors in the medium [39, 40]. Subsequent work concluded that this was not solely a consequence of growth factor exhaustion and was instead due to the ability of cell–cell adhesion to either directly or indirectly inhibit the response to serum growth factors [41]. These studies
Ideas for the future: adhesion receptors, the cytoskeleton and mechanotransduction in CIP
In summary, we are seeing rapid progress in understanding the molecular bases of CIP. In the process, it is abundantly clear that the cellular phenomenon of contact-induced proliferative inhibition entails the cell's ability to integrate multiple upstream cues, including adhesion receptors, that funnel down to modulate core signaling pathways. In considering the impact of cell–cell adhesion, we would also highlight the importance of adhesive interactions as active, mechanical processes that
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank members of the Yap and McClatchey labs for fruitful discussions. A.I.M. is supported by National Institutes of Health Grants (R01GM087558, R01CA113733) and an MGH Research Scholars Award. A.S.Y. is supported by project grants and a Research Fellowship from the National Health and Medical Research Council of Australia.
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