Abstract
Numerous experimental studies demonstrate that the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) Ras homolog family member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42) are important regulators in somatosensory neurons, where they elicit changes in the cellular cytoskeleton and are involved in diverse biological processes during development, differentiation, survival and regeneration. This review summarizes the status of research regarding the expression and the role of the Rho GTPases in peripheral sensory neurons and how these small proteins are involved in development and outgrowth of sensory neurons, as well as in neuronal regeneration after injury, inflammation and pain perception. In sensory neurons, Rho GTPases are activated by various extracellular signals through membrane receptors and elicit their action through a wide range of downstream effectors, such as Rho-associated protein kinase (ROCK), phosphoinositide 3-kinase (PI3K) or mixed-lineage kinase (MLK). While RhoA is implicated in the assembly of stress fibres and focal adhesions and inhibits neuronal outgrowth through growth cone collapse, Rac1 and Cdc42 promote neuronal development, differentiation and neuroregeneration. The functions of Rho GTPases are critically important in the peripheral somatosensory system; however, their signalling interconnections and partially antagonistic actions are not yet fully understood.
Highlights
The members of the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) are small GTP binding and hydrolysing proteins of approximately 21 kDa, which together with ADP ribosylation factors (Arfs), Ras-related proteins in brain (Rab), Ras-related nuclear protein (Ran) andRas belong to the Ras superfamily of small GTPases [1]
Rac GTPases seem to have anti-apoptotic properties promoting neuronal survival acting on two signalling pathways: on one hand by activating the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal–regulated kinase 1/2 (ERK1/2) signalling cascade, which represses the induction of the pro-apoptotic BH3-only protein Bim in an c-Jun N-terminal kinase (JNK)/c-Jun-dependent matter and on the other hand, by inhibiting the Janus kinase (JAK)/signal transducer and activator of transcription 5 (STAT5) signalling cascade that represses anti-apoptotic B-cell lymphoma-extra-large (Bcl-xL) [94,95,96,97]
In sensory neurons and conditions related to neuronal development, differentiation, migration and regeneration, Ras homolog family member A (RhoA) limits these processes and reduces regeneration through growth cone collapse and neurite retraction, while related C3 botulinum toxin substrate 1 (Rac1)/cell division cycle 42 (Cdc42) promote a favourable environment for neuronal regeneration
Summary
The members of the Ras homolog family of guanosine triphosphate hydrolases (Rho GTPases) are small GTP binding and hydrolysing proteins of approximately 21 kDa, which together with ADP ribosylation factors (Arfs), Ras-related proteins in brain (Rab), Ras-related nuclear protein (Ran) and. Rho GTPase PTMs, such as phosphorylation, ubiquitylation and sumoylation, determine their localization but may directly affect their function [25]. Rho GTPases act on their numerous downstream effectors, including among others serine/threonine kinases, such as Rho-associated protein kinase (ROCK) and protein kinase C-related kinase (PRK) for the Rho subfamily, p21-activated kinase (PAK) and mixed-lineage kinase (MLK) for the Rac subfamily and tyrosine kinases, such as activated Cdc42-associated tyrosine kinase (ACK) for the Cdc subfamily. Lipid kinases,—for example, Phosphoinositide 3-kinase (PI3K)—are downstream effectors for Rac and Cdc subfamilies kinase (ROCK) and protein kinase C-related kinase (PRK) for the Rho subfamily, p21-activated kinase (PAK) and mixed-lineage kinase (MLK) for the Rac subfamily and tyrosine kinases, such as activated. Subfamilies, respectively (for a review see Reference [36])
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