Primary immunodeficiencies (PIDs) are associated with deleterious mutations of genes that encode proteins involved in actin cytoskeleton reorganisation. This deficiency affects haematopoietic cells. PID results in the defective function of immune cells, such as impaired chemokine-induced motility, receptor signalling, development and maturation. Some of the genes mutated in PIDs are related to small Ras homologous (Rho) guanosine triphosphatase (GTPase), one of the families of the Ras superfamily. Most of these genes act as molecular switches by cycling between active guanosine triphosphate-bound and inactive guanosine diphosphate-bound forms to control multiple cellular functions. They are best studied for their role in promoting cytoskeleton reorganisation, cell adhesion and motility. Currently, only three small Rho GTPases, namely, Rac2, Cdc42 and RhoH, have been identified in PIDs. However, several other Rho small G proteins might also contribute to the deregulation and phenotype observed in PIDs. Their contribution in PIDs may involve their main regulator, Rho guanine nucleotide exchange factors such as DOCK2 and DOCK8, wherein mutations may result in the impairment of small Rho GTPase activation. Thus, this review outlines the potential contribution of several small Rho GTPases to the promotion of PIDs.
Cdc42 is a member of the Rho family of small GTPases and a master regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. This small G protein and its regulators have been the subject of many years of fruitful investigation and the advent of functional genomics and proteomics has opened up new avenues of exploration including how it functions at specific locations in the cell. This has coincided with the introduction of new structural techniques with the ability to study small GTPases in the context of the membrane. The role of Cdc42 in cancer is well established but the molecular details of its action are still being uncovered. Here we review alterations found to Cdc42 itself and to key components of the signal transduction pathways it controls in cancer. Given the challenges encountered with targeting small G proteins directly therapeutically, it is arguably the regulators of Cdc42 and the effector signalling pathways downstream of the small G protein which will be the most tractable targets for therapeutic intervention. These will require interrogation in order to fully understand the global signalling contribution of Cdc42, unlock the potential for mapping new signalling axes and ultimately produce inhibitors of Cdc42 driven signalling.
Ras-homologous (Rho) guanosine triphosphatases (GTPases) are considered a central player in regulating various biological processes, extending to immune regulation. Perturbations in Rho GTPase signalling have been implicated in immune-related dysregulation, contributing to the development of autoimmunity. This study presents a scientometric analysis exploring the interlink between the Rho GTPase signalling system and autoimmunity, while also delving into the trends of past studies. A total of 967 relevant publications from 1990 to 2023 were retrieved from the Web of Science Core Collection database after throrough manual filtering of irrelevant articles. The findings show an upward trajectory in publications related to this field since 2006. Over the past three decades, the United States of America (41.68%) emerged as the primary contributor in advancing our understanding of the association between the Rho GTPase signalling system and autoimmunity. Research in autoimmunity has mainly centered around therapeutic interventions, with an emphasis on studying leukocyte (macrophage) and endothelial remodelling. Interestingly, within the domains of multiple sclerosis and rheumatoid arthritis, the current focus has been directed towards comprehending the role of RhoA, Rac1, and Cdc42. Notably, certain subfamilies of Rho (such as RhoB and RhoC), Rac (including Rac2 and RhoG), Cdc42 (specifically RhoJ), and other atypical Rho GTPases (like RhoE and RhoH) consistently demonstrating compelling link with autoimmunity, but still warrants emphasis in the future study. Hence, strategic manipulation of the Rho signalling system holds immense promise as a pivotal approach to addressing the global challenge of autoimmunity.
Activated Cdc42-associated kinase (ACK), a non-receptor tyrosine kinase, is an effector for the small GTPase Cdc42. ACK is emerging as an important component of the cancer landscape and thus, a promising target for the treatment of many malignancies. ACK is also being increasingly recognized as a potentially influential player in the regulation of protein homoeostasis. The delicate equilibrium between protein synthesis and protein degradation is crucial for healthy cell function and dysregulation of protein homoeostasis is a common occurrence in human disease. Here, we review the molecular mechanisms by which ACK regulates the stability of diverse cellular proteins (e.g. EGFR, p27, p53, p85 isoforms and RhoGDI-3), some of which rely on the kinase activity of ACK while others, interestingly, do not. Ultimately, further research will be required to bridge our knowledge gaps and determine if ACK regulates the stability of further cellular proteins but collectively, such mechanistic interrogation would contribute to determining whether ACK is a promising target for anti-cancer therapy. In therapeutics, proteasome inhibitors are an efficacious but problematic class of drugs. Targeting other modulators of proteostasis, like ACK, could open novel avenues for intervention.
Herbal treatments have been utilized for millennia to cure a variety of ailments. There are over 20, 000 herbal remedies available to treat cancer and other disease in humans. In Ayurveda, traditional plants having revitalizing and nourishing characteristics are known as "Rasayanas." They have anti-inflammatory, anticancer, anti-microbicidal, antiviral, and immunomodulatory effects on the immune system. Immunomodulation is a mechanism through which the body stimulates, suppresses, or boosts the immune system to maintain homeostasis. Plant-derived immunomodulators are typically phytocompounds, including carbohydrates, phenolics, lipids, alkaloids, terpenoids, organosulfur, and nitrogen-containing chemicals. Immunomodulation activity of phytocompounds from traditional plants is primarily mediated through macrophage activation, phagocytosis stimulation, peritoneal macrophage stimulation, lymphoid cell stimulation, and suppression or enhancement of specific and non-specific cellular immune systems via numerous signalling pathways. Despite extensive research, the precise mechanism of immunomodulation of most traditional plants has not yet been fully elucidated, justifying the need for further experimentation. Therefore, this review describes the immunomodulatory agents from traditional plants such as Curcuma longa L., Panax ginseng C.A. Meyer, and Moringa oleifera Lam, further highlighting the common molecular targets and immunomodulatory mechanism involved in eradicating diseases.