The ATPases Associated with Diverse Cellular Activities (AAA ATPases) represent a family of enzymes found in all domains of life which share a conserved ATP binding domain, known as the AAA + module. This structurally conserved domain is generally 200–250 residues long and contains the classical Walker A and Walker B motifs which are involved in ATP binding and hydrolysis [5,6]. The active form of AAA ATPases typically requires oligomerization into ring shaped complexes, which then proceed to harness the energy of ATP hydrolysis to catalyze numerous cellular functions, as reflected by the enzyme family name [7]. These functions include roles in protein degradation and quality control, DNA replication and maintenance of genomic stability, membrane fusion, microtubule regulation, organelle biogenesis, cellular division, and chromatin organization [7,8] (Figure 1a). The functional regulation of AAA ATPases is an important area of ongoing investigation, both with regards to control of intrinsic ATPase activity, and simultaneous coordination of multifunctionality within the cellular context. These regulatory processes stem from quaternary structural consequences of the numerous protein–protein interactions (PPIs) established by AAA ATPases [9].

AAA ATPases utilize ATP hydrolysis to accomplish versatile cellular functions with the engagement of several multiprotein complexes that are assembled on the ring-shaped proteins [10, 11, 12, 13, 14, 15]. Further evidence that binding partners of AAA ATPases play a pivotal role in coordinating and organizing cellular functions is implied by the correlation between number of binding partners and number of observed cellular functions (Figure 1b and Table 1).

Cancer cells rely on an upregulated metabolic state while balancing genomic instability due to the acquisition of oncogenic and malignant mutations. To meet these increased metabolic demands and to maintain proteomic and genomic homeostasis, a variety of candidate proteins are often expressed at higher levels. Some of these include AAA ATPases which function in DNA repair, protein degradation and homeostasis, and other cellular processes [16]. AAA ATPases are potential biomarkers of specific cancer types [4] and therefore, represent attractive therapeutic targets [17, 18, 19, 20, 21, 22, 23]. While inhibitors of AAA ATPase activity could disrupt functionality at a global level, with the potential for numerous off-target effects, inhibition that is specific to the interacting proteins offers better selectivity [24]. Due to the large interactome that these AAA ATPases possess, each PPI contributes to the expansive functionality of these proteins. Therefore, targeted inhibition of AAA ATPase PPIs may be achieved through selective disruption of function-specific complexes [24] (Figure 1a). VCP/p97 (referred to as p97 in the rest of the text) and RUVBL1/2 are two members of the AAA ATPase family that are especially promiscuous and interact with a variety of proteins to achieve diverse functions (Figure 1b). This review highlights selected PPIs established by these two ATPases that may be targeted in the context of cancer therapy.