We all know that a cell is structured in three main essential components, that are the nucleus, the cytoplasm and the membrane. However, what is there outside the cell membrane? Although the answer to this question may depend on the type of cell we are looking at, generally animal cells are surrounded by an intricated 3D network of macromolecules (proteins and carbohydrates) called the extracellular matrix (ECM).
ECM molecular composition
Considering that the ECM consists of several different macromolecules that have different functions, we can easily deduce that the ECM plays various roles. A well-known role of the ECM is providing structural support for single cells as well as for tissues and organs. It also modulates different biological processes such as cell differentiation and migration, and tissue morphogenesis, repair and homeostasis. Indeed, the ECM is highly dynamic and undergoes remodelling during injury and repair.
The two main classes of macromolecules which the ECM is made of are fibrous proteins (collagens, fibronectins, elastins and laminins) and proteoglycans (PGs). Collagens are the most abundant fibrous proteins of the ECM and play a key role in maintaining tissue structural integrity. Human genetic disorders affecting collagen (e.g. Ehlers-Danlos syndrome) lead to fragile tissues which tear too easily. Collagen proteins usually organise their structure into long fibres called fibrils. Fibrils intersect with different molecules, including elastin, another essential ECM fibrous protein that allows tissues to recoil after repeated stretch.
Collagen fibrils also link to PGs, which fill the majority of the ECM interstitial space within the tissue and form a hydrated gel that has mechanical buffering, force-resistance and hydration properties. Indeed, PGs are extremely hydrophilic molecules which adopt extended conformations enabling the ECM to sustain high compressive forces.
A third fibrous protein, fibronectin (FN) is intimately involved in directing the organisation of the interstitial ECM and, additionally, has a crucial role in mediating cell attachment and function. FN can be stretched several times over its resting length by cellular traction forces. Such force-dependent unfolding of FN exposes cryptic integrin-binding sites within the molecule that result in pleiotropic changes in cellular behaviour and implicate FN as an extracellular mechano-regulator. FN is also crucial for cell migration during development and has been involved in cardiovascular disease and tumour metastasis.
Integrins – the mechanistic link between ECM and cytoskeleton
ECM interacts with the cytoplasm through surface receptors called integrins. Integrins function mechanically, attaching the ECM to the cytoskeleton, and biochemically, sensing when adhesion has occurred. Integrins are adhesion receptors that function bidirectionally, transmitting biochemical signals both outside-in and inside-out the cell. Integrin proteins are heterodimers which consist of an alpha (α) and a beta (β) subunits, linked by noncovalent interactions, which form an extracellular head, a transmembrane body and two cytoplasmic tails.
The β-tail binds to various protein adaptors, which promote linkage to actin. Three main protein adaptors are interacting with integrin β-tail:
-Structural adaptors, such as tensin and talin, which directly link integrins to the cytoskeleton;
-Scaffolding adaptors, such as paxillin, which build bridges among focal adhesion proteins;
-Catalytic adaptors, such as integrin-linked kinase (ILK) and focal adhesion kinase (FAK), which transduce signals from adhesion sites.
What determines which adaptor binds integrins is the phosphorylation state of cytoplasmic tail residues, that leads to subsequent downstream interactions and response of integrins.
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