Cell polarity is a structural and functional specialization that is ubiquitous in biology. The commonality of polarity across the phyla reflects a fundamental requirement of individuals to localize different activities to distinct regions of cells, especially when individual cells come together to form complex multicellular tissues. The specialized domains of the plasma membrane that result from polarization determine cell orientation, function and fate. For example, polarization enables long-range communication by neurons and short-range communication in the immune system, vectorial transport of ions across epithelial cells and niche-specific orientation of stem-cell division, which specifies the developmental fate of daughter cells.
At first glance, the fact that different cell types exhibit diverse polarized phenotypes implies that a diverse array of specialized machineries has evolved. However, it seems that simple variations of common mechanistic themes result in the unique shapes, asymmetries and functions that characterize polarized cells and tissues. First, intrinsic protein-sorting codes are recognized and segregated by cytoplasmic adaptor complexes that regulate protein trafficking to plasma membrane domains. Second, signalling complexes and scaffolds become differentially associated with the cytosolic face of the membrane, where they define and stabilize the biochemical features of resulting domains. Third, adhesion receptors that detect neighbouring cells and the extracellular matrix (ECM) provide cues that orientate cells in three-dimensional (3D) space.
Two considerations support the idea that cell polarity is achieved through the integration of these three conserved molecular mechanisms. First, all eukaryotic cells share common cellular machineries for post-translational protein trafficking and compartmentalization1
. Second, cells can adopt different shapes and functions in response to specific physiological contexts. For example, during embryogenesis, a single cell can change its shape and function as it migrates, according to morphogenetic gradients, and can then repolarize on detecting transcriptionally specified cell–cell interactions2
. In disease states, such as cancer, epithelial cells lose polarity (through epithelial– mesenchymal transition (EMT)), disengage from multicellular interactions, migrate and then reintegrate into a second tissue, in which they undergo structural and functional reorganization to reside at the new site3,4
. Thus, the dynamics and plasticity of the loss and re-establishment of polarity suggest that common machineries of membrane traffic are used at all times, but are deployed differently depending on the physiological context.
Here, we summarize the basic cellular machineries and biochemical rules that control the delivery of protein components to different plasma membrane domains in a generic polarized cell. We then describe the spatial cues and signalling pathways that organize these basic machineries to produce various cell shapes and functions. Finally, we consider how component asymmetry at the single-cell level is orientated in 3D space to define polarity in complex tissues. We emphasize how these different pathways generate plasticity in the forms of cell polarity, and how defects underlie important pathological states. Although much has been learnt about each of these three mechanisms in isolation, understanding how they are integrated and coordinated into a network remains a central challenge — one that is fundamental to understanding organogenesis, tissue function and various pathological states.