Integrins

INTRODUCTION

These are transmembrane cell adhesion molecule that helps in conveying signaling by binding to ligands present in the extracellular matrix and to the cytoskeleton microtubules present in the cytoplasm. They are also responsible for cell shape, activating intracellular signaling, such as signaling in platelets for interaction with coagulation factors. Commonly known integrins are collagen, fibronectin, laminins, etc. They are also important for activation of some ligands/signaling molecules, for example, integrin-dependent activation of TGF Beta responsible for apoptosis and cell arrest. Their attachment with ligands based upon the "Velcro principle," i.e., the attachments are through many weak bond interactions. These interactions are not too strong, as in the case of strong interactions, integrin molecules will glue to the ECM. So these integrins bind to their ligand with lower affinity.

STRUCTURE

Integrins are heterodimers that consist of two glycoprotein subunits (α and β). There are a total of 18 different alpha and 8 different beta types of subunit coded by the human genome. Both subunits penetrate across the plasma membrane, bound to each other and contain a binding site for ligand in the matrix site (N-Terminal) in alpha as well as in beta subunit, and cytosolic binding in beta subunit (C-Terminal), e.g., RGD sequence of fibronectin binds to the matrix site and talin binds to the cytosolic site (α-actinin also binds here). Variants or isoforms of integrin molecules can be present in the body due to alternative splicing of mRNA. Their mass can vary from 90 kDa to 160 kDa, whereas β-4 has a higher mass due to an exceptionally longer 1088 amino acid sequence. Both subunits contain a binding domain for divalent ions such as Ca+2, Mg+2, but their function is unknown in the alpha subunit, whereas they are involved in direct interaction with ligand binding sites in the β subunit. The binding of metal ions is through a particular site, which is called MIDAS (Metal Ion Dependent Adhesion Site). Through MIDAS, the I-like domain of α and β subunit of integrin binds together with the ligand which causing its dimerization, though till now it is inactive due to the presence of electrostatic salt bridges present between the two subunits. The cytosolic domain of the β subunit contains a motif (NPxY/F) that binds to the adapter protein; this binding activates the integrin molecule by breaking salt bridges present between the two subunits.

FUNCTION

Integrins have two main functions

a) Attachment of the Cell to the ECM, 

b) Signal Transduction from the ECM to the Cell

a) Interaction with Cytoskeleton to enhance binding of Cell to ECM – Integrins work as a linkage between the extracellular matrix and cytoskeleton to form a cell grip as they bind to actin filaments in cytoplasm or cell cortex. Only one integrin is bound to intermediate filament, i.e., α6β4, which is an exception. In the matrix phase (N-Terminal side), integrin is bound to ligand, and subsequently it binds to the adapter protein in the cytosolic phase (C-Terminal side), which works as an attachment between the cytoskeleton and extracellular matrix (ECM). Slowly, many integrins form clusters where they together form a focal adhesion, which joins the ECM to the cell, thus regulating the shape and movement of the cell. These focal adhesions are temporary, but they form Cell-Matrix Adhesion just like cadherins form Cell-Cell Interaction/Adhesion. Gene knockout for the β subunit results in a shortened integrin that can still bind to ligand in the ECM but does not bind to the adapter protein in the cytosolic phase.

b) Integrins regulate various Pathways by interacting with different ligands – In developing nerve,e activated integrin can induce signal response on its own axon body rather than cell-cell interaction. Their activity depends upon FAK (Focal Adhesion Kinase), which is a cytoplasmic tyrosine kinase. When integrins cluster together, they recruit FAK, which binds to the beta subunit, talin (which is already bound to the beta subunit) or, rarely, to paxillin (which is bound to the alpha subunit). Now, these FAK molecules cross-phosphorylate each other, which induces a signaling pathway for the Src family. Src family is another cytoplasmic tyrosine kinase protein. These Src family further phosphorylates the FAK molecule in the extra region for the recruitment of extra protein kinase enzymes for further processes. By this mechanism, integrins play an important role in the relay of the message for a longer duration. Mutant mice for FAK (knockout mice for the FAK gene) that have FAK protein deficiency in fibroblasts produce too many focal adhesions rather than few. This gives the sense that FAK helps in the disassembling of focal adhesion rather than assembling.