cdc42: cell division control homolog 42
Introduction - The biological role of cell division control homolog 42 (cdc42)
Our assigned molecule is cell division control homolog 42 (cdc42) isoform 1 (AF498962_1)
Diagrammatic representation of major signalling cascades of a vast array of molecules and the biological importance of cdc42 (in box) in cell signalling
cdc42 is a Rho-GTPase implicated in the control of several disparate signalling cascades in cytokinesis, mitotic cycle progression, endocytosis and cellular morphology. It alternates between an active conformation when bound to GTP and an inactive state when GDP is bound, in a closely regulated cycle. In this cycle guanine nucleotide exchange factors (GEFs) act as the molecular switches activating cdc42 by catalysing the exchange of bound-GDP for GTP and GTPase activating proteins (GAPs) stimulate signal transduction termination by promoting the GTPase activity of cdc42 switching bound-GTP for GDP.
cdc42 is involved in all stages of mitotic cell division but it has been found that GTP-cdc42 peaks in metaphase; when the chromosomes align as it is an essential driver of Rho-signalling cascades; with RhoA-mediated signalling being crucial for cytokinesis [Figure 1]. During metaphase, it is important in the correct orientation of the mitotic spindle and centrosomes which are vital for the correct chromosomal alignment and planar division. cdc42 also functions as a key regulator of cell polarity, endothelial organs’ formation and additionally maintains centrosome integrity. Furthermore, the cdc42/mDia3 signalling cascade is entangled in the proper bi-oriented microtubule attachment to the kinetochores for the correct alignment and segregation of chromosomes during the metaphase stage.
Figure 1. cdc42 signalling cascades during prometaphase and metaphase at the mitotic spindle and centrosomes. cdc42 drives several pathways that lead to the correct spindle orientation, assembly, stabilization and attachment to the kinetochores.
Recent studies have linked elevated cdc42 levels in hematopoietic stem cells (HSCs) as a causative agent of increased morbidity and aging. Tissues extracted from animals were examined when the cdc42 gene activity was upregulated and found to age prematurely, including HSCs. These studies demonstrate the fact that this small Rho-GTPase plays a crucial role in the aging process of HSCs and any disturbances in its physiological levels can prove detrimental to the survival of these cells. In addition, cdc42 regulates cell growth signalling by interacting with the JAK-STAT signalling cascade and by promoting activation of several molecules, in between others the Erk, JNK and MAP kinases. Moreover, it has been suggested that cdc42 possibly couples its functions in the cell division and growth by acting via the cdc42-IQGAP1-mTOR signalling pathway. In addition cdc42 is thought to have integral functions in a multitude of systemic organs such as the pancreas, the heart and the nervous system by signalling through multiple pathways.
Furthermore, more recent research outcomes have shown that cdc42 is also rather important in neuronal morphology including, spine morphogenesis, growth cone development and axon guidance. cdc42 and in general Rho-GTPases have been linked with neuronal survival and death regulation, by promoting either pro-survival or pro-apoptotic signalling cascades. This novel function of Rho-GTPases, in this instance cdc42, warrants further investigation as they may underscore the causation of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s and amyotrophic lateral sclerosis. Moreover, its upregulation has been shown to underlie many major forms of cancer such as lymphomas, lung cancer and breast cancer.
What can be deducted is that cdc42 is a molecule of paramount importance, that exerts a non-redundant role in controlling a diverse array of cellular activities. Abnormal expression of this signalling mediator can have adverse functional repercussions in human health.
References
1. Chircop, M. 2014. Rho GTPases as regulators of mitosis and cytokinesis in mammalian cells. Landes bioscience. 5(2):29770
5. Sadok A. and Marshall CJ. 2014 Rho GTPases: masters of cell migration. Landes bioscience 5(4) 1-7