Abstract
Calmodulin is a ubiquitous signalling protein that controls many biological processes due to its capacity to interact and/or regulate a large number of cellular proteins and pathways, mostly in a Ca2+-dependent manner. This complex interactome of calmodulin can have pleiotropic molecular consequences, which over the years has made it often difficult to clearly define the contribution of calmodulin in the signal output of specific pathways and overall biological response. Most relevant for this review, the ability of calmodulin to influence the spatiotemporal signalling of several small GTPases, in particular KRas and Rac1, can modulate fundamental biological outcomes such as proliferation and migration. First, direct interaction of calmodulin with these GTPases can alter their subcellular localization and activation state, induce post-translational modifications as well as their ability to interact with effectors. Second, through interaction with a set of calmodulin binding proteins (CaMBPs), calmodulin can control the capacity of several guanine nucleotide exchange factors (GEFs) to promote the switch of inactive KRas and Rac1 to an active conformation. Moreover, Rac1 is also an effector of KRas and both proteins are interconnected as highlighted by the requirement for Rac1 activation in KRas-driven tumourigenesis. In this review, we attempt to summarize the multiple layers how calmodulin can regulate KRas and Rac1 GTPases in a variety of cellular events, with biological consequences and potential for therapeutic opportunities in disease settings, such as cancer.
Highlights
Calmodulin is a ubiquitously expressed small protein (148 amino acids) and considered the most important Ca2+ sensor in non-muscular cells [1,2]
Conformational changes may lead to differential sensitivity towards the GTP/GDP ratio in the different models and experimental settings analyzed, possibly allowing the hypervariable region (HVR) domain to interact with Ca2+/calmodulin, even when GDP is bound to Kirsten Ras (KRas)
protein kinase C (PKC) or calmodulin interacting with KRas have consequences for the cellular location of KRas, as serine 181 (Ser181) phosphorylation alleviates the electrostatic interaction with the plasma membrane
Summary
Calmodulin is a ubiquitously expressed small protein (148 amino acids) and considered the most important Ca2+ sensor in non-muscular cells [1,2]. More than 450 calmodulin interacting proteins in human and mice have been described (BioGRID: https//thebiogrid.og; [9]), suggesting multiple cellular pathways that are triggered or regulated by calmodulin This large and diverse group of CaMBPs includes enzymes such as kinases and phosphatases, ion channels, and cell surface receptors. These interactions control the spatiotemporal localization, activity, and biological outcome of GTPase signalling. GEF proteins stimulate GDP dissociation, enabling the GTPase to incorporate GTP, which is 10-fold more concentrated than GDP in the cytosol This turns the GTPase into an active state, capable of interacting with effectors to activate pathways that determine multiple aspects of cellular behavior. The latter has been recently reviewed in more detail in a previous issue of this journal [27,28]
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