Clutching at Guidance Cues: The Integrin–FAK Axis Steers Axon Outgrowth

SIMPLE SUMMARY: Neurons are biological wires that send signals not only across the brain, but throughout the body. Like almost all cells in the human body, neurons adhere to their surroundings through receptors known as integrins. As the nervous system develops, integrins become essential for neuronal wires, known as axons, to adhere within their environment and pull themselves forward as they grow towards their target. Following injury to the nervous system, the damaged axons must regrow towards their target to restore communication. The integrin receptor therefore plays an important role in this process of regeneration. Integrins mediate their effects through an intricate scaffold of proteins inside the cell, which must be coordinated by a specific central protein, called focal adhesion kinase. This review discusses the signalling pathway of integrin receptors and focal adhesion kinase, specifically in neurons, and how this signalling pathway mediates neuronal growth. We also discuss how integrins and focal adhesion kinase could contribute to neuronal repair following nervous system injury. ABSTRACT: Integrin receptors are essential contributors to neurite outgrowth and axon elongation. Activated integrins engage components of the extracellular matrix, enabling the growth cone to form point contacts, which connect the extracellular substrate to dynamic intracellular protein complexes. These adhesion complexes facilitate efficient growth cone migration and neurite extension. Major signalling pathways mediated by the adhesion complex are instigated by focal adhesion kinase (FAK), whilst axonal guidance molecules present in vivo promote growth cone turning or retraction by local modulation of FAK activity. Activation of FAK is marked by phosphorylation following integrin engagement, and this activity is tightly regulated during neurite outgrowth. FAK inhibition slows neurite outgrowth by reducing point contact turnover; however, mutant FAK constructs with enhanced activity stimulate aberrant outgrowth. Importantly, FAK is a major structural component of maturing adhesion sites, which provide the platform for actin polymerisation to drive leading edge advance. In this review, we discuss the coordinated signalling of integrin receptors and FAK, as well as their role in regulating neurite outgrowth and axon elongation. We also discuss the importance of the integrin–FAK axis in vivo, as integrin expression and activation are key determinants of successful axon regeneration following injury.