Integrins promote axonal regeneration after injury of the nervous system - PubMed (original) (raw)

Molecular mechanisms of integrin inactivation after trauma in the nervous system. Integrins at the growth cones of regenerating axons are exposed to the extracellular environment of the lesion site. Integrins recruit focal adhesion kinases (FAKs) among others, which in turn, activate downstream signalling molecules such as protein kinase B (Akt3), phosphoinositide 3‐kinase (PI3K), Ras homolog gene family member A (RhoA), and Src kinase. However, most integrins exist in a bent, inactive state at the cell surface. The lesion site is rich in axon‐repulsive molecules, including Nogo‐A, myelin‐associated glycoprotein (MAG), class III semaphorins (Sema3s), and chondroitin sulphate proteoglycans (CSPGs). These molecules bind to several receptors, such as leukocyte common antigen‐related phosphatase (LAR), Nogo receptors (NgR1, NgR2), the plexin/neuropilin (PLXN/NRP) complex and protein tyrosine phosphatase σ (PTPσ), to suppress integrin signalling and axon regeneration. Nogo‐A binds to NgR1 and inhibits the phosphorylation of FAK. MAG is a direct ligand for integrins and stimulates integrin signalling. However, MAG also has an opposing effect by NgRs signalling that indirectly elevates intracellular calcium levels and stimulates clathrin‐mediated endocytosis of integrins. Most Sema3s mediate signalling

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the PLXN/NRP receptor complex that results in inactivation of R‐Ras, which in turn interferes with integrin signalling, and activates ADP‐ribosylation factor 6 (ARF6) to remove integrins from the cell surface. Sema3A signalling results in the phosphorylation (Tyr397, Tyr576, Tyr577, Tyr925) and de‐phosphorylation (Tyr407, Tyr861) of different residues of FAK for Sema3A‐mediated axonal remodelling. CSPGs interact with many receptors, including LAR, NgR1 and PTPσ. The CSPG aggrecan has been shown to reduce FAK signalling, but the exact mechanisms remain to be identified. Other ligands such as ephrins, netrins and slits are also known to interfere with integrin signalling. In addition, there is evidence that integrin activation by kindlins and talins is inhibited by various regulatory mechanisms (illustrated as x).