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Cell polarity refers to the intrinsic asymmetry observed in cells, either in their shape, structure, or organization of cellular components. Most epithelial cells, migrating cells and developing cells require some form of cell polarity for their function. These cells receive information about their surroundings via extracellular biochemical and mechanical cues and translate those information into polarity of the plasma membrane, its associated proteins and cytoskeletal organization. Once established, cell polarity is maintained by transcytosis, in which vesicles carry incorrectly-localized membrane proteins to the correct regions in the plasma membrane. In addition, tight junctions, which act as ‘fences’ against transmembrane diffusion, lock the asymmetry in place. Therefore, mechanobiology plays an essential regulatory role in both the establishment and maintenance of cell polarity. More details on the barrier or ‘fence’ functions of tight junctions can be found here.
Epithelial cells establish an apical-basal polarity, which results from the differential distribution of phospholipids, protein complexes, and cytoskeletal components between the various plasma membrane domains, reflecting their specialized functions. The membrane facing the lumen or free surface is known as the apical membrane, while the membrane oriented away from the lumen, contacting the extracellular matrix, is known as the basal membrane and the sides of the cell contacting the neighboring cells form the lateral membrane . The apico-basal polarization of epithelial cells is known to be a pre-requisite for their fundamental biological roles. These include regulating the vectorial transport of ions across cell sheets during their barrier function as well as ensuring directionality during their secretory and absorptive functions .
In other specialized cells such as immune cells and neurons, cell polarity enables the short-range and long-range transmission of various electrical and biochemical signals. For instance, A typical unipolar neuron has a highly distinctive shape and structure, with one end adapted to receive signals through highly branched dendrites. This signal is then transmitted down an axon, which can stretch the length of the body. At the other end of the cell is the axon terminal, where the synapses are located. These synapses can release chemical neurotransmitters in order to propagate the signal or effect an action such as muscle contraction.
In polarized epithelial cells, the apical membrane is rich in PIP2 and houses the PAR and Crumbs polarity complexes while the basal membrane contains PIP3 and the Scribble polarity complex . The phosphatase PTEN, which is recruited by tight junction proteins such as Magi 1-3, stabilizes PIP2 distribution at the apical membrane by reversing PI3K-mediated phosphorylation of PIP2 to PIP3 . This is essential for maintaining cell polarity, as studies involving the addition of exogenous PIP3 to the apical surface of polarized cells resulted in a quick inversion of polarity . PAR3 also contributes to the maintenance of phosphoinositide distribution at the apical membrane by binding simultaneously to both PIP3 and PTEN via its PDZ2 and PDZ3 domains, respectively. This results in PIP3 being trapped in the apical domain, followed by its instant hydrolysis to PIP2 by PTEN . Additionally, the ‘fence’ function of the tight junctions also helps in restricting PIP2 and PIP3 to distinct membrane domains by preventing the free diffusion of PTEN and PI3K between the apical and basolateral membranes .
The three main protein complexes defining cellular polarity, namely the Scribble (Scrib/Dlg/Lgl), Crumbs (Crb/Pals1/PatJ), and PAR (Par3/Par6]/a-PKC) polarity complexes interact with each other as well as with a number of cytoskeleton-associated proteins to regulate cellular polarity . While the PAR and the Crumbs complexes are restricted at the apical surface, Scribble complex is localized to the basolateral domain and the three complexes interact in a cooperative and/or antagonistic manner to fine-tune localized signals. The polarity complexes take their localization cue from the adherens junctions and tight junctions. For instance, Par3 localizes to the tight junctions by binding to the junctional adhesion molecules (JAMs) via its PDZ1 domain , while local Cdc42 and Rac activation at the AJs serve to recruit a-PKC to the apical surfaces .
As well as the asymmetric organization of cellular components, polarity can also be defined through the structural orientation of the cytoskeleton, in particular, actin filaments and microtubules. This is important in cell migration and motility, which requires a front-rear polarity in order to determine the direction of movement. Both actin and microtubules are polar, dynamic filaments formed of protein subunits. These subunits associate together and align in the same direction to form a polymer which has two distinct ends. These actin filament polymers and microtubule polymers are therefore intrinsically polar, and cytoskeleton-associated proteins can use this asymmetry for further biological functions. Motor proteins such as myosins, kinesins, and dynein catalyze unidirectional movement along actin or microtubules to transport cargo throughout the cell, and this process can also generate polarity through organization of cellular components . For instance, dynein has been associated with the transport of both Par3 and the Crumbs polarity protein to the apical region of the cell .
One of the first signals that initiates polarized actin cytoskeletal remodeling arises from the binding of extracellular matrix components to the integrin receptors on the basal plasma membrane. Integrin signaling activates Rac1 , which is involved in the organization of laminin within the basement membrane . In addition, activated Rac1 binds to the adaptor protein IRSp53 and causes the local activation of actin polymerization factors, which are then responsible for assembling a basal actin cortex . At the apical surface, signaling via adherens junctions recruits c-Src, which results in a similar activation of actin polymerization modules through Rac and Cdc42 GTPases . Several studies have also demonstrated the involvement of integrin-based adhesions and adherens junctions in the recruitment and polarized orientation of microtubules. In this regard, integrin-linked kinase (ILK) activated by integrin-beta1 signaling activates microtubule plus ends via adaptor proteins such as APC . The minus ends of microtubules in fully polarized epithelia cluster at the adherens junctions, where they are stabilized by proteins like ninein . Another recently-characterized protein CAMSAP3 (also known as Nezha) was found to tether the microtubule minus ends to the apical cortex .
When a cell is unable to polarize correctly, the resulting loss or mutation of function can lead to disease. Some cell polarity defects include cystic fibrosis, cardiac arrhythmia and oncogenesis . One protein which has been implicated in tumour invasion is AmotL2, a membrane associated scaffold protein that regulates expansion of the aortic lumen. Stress related activation of AmotL2 disrupts apical/basal polarity by preventing PAR and Crumb complexes from reaching the apical membrane, leading to tumour formation and invasion .