IQ Motif Containing GTPase Activating Proteins (IQGAPs), A-Kinase Anchoring Proteins (AKAPs) and Kinase Suppressor of Ras Proteins (KSRs) in Scaffolding Oncogenic Pathways and Their Therapeutic Potential

Abstract

Scaffolding proteins colocalize interacting partners on their surface and facilitate complex formation. They have multiple domains and motifs, which provide binding sites for various molecules. This property of scaffolding proteins helps in the orderly transduction of signals. Abnormal signal transduction is frequently observed in cancers, which can also be attributed to the altered functionality of scaffolding proteins. IQ motif containing GTPase activating proteins (IQGAPs), kinase suppressor of Ras (KSR), and A-kinase anchoring proteins (AKAPs) tether oncogenic pathways RAS/RAF/MEK/ERK, PI3K/AKT, Hippo, Wnt, and CDC42/RAC to them. Scaffolding proteins are attractive drug targets as they are the controlling hub for multiple pathways and regulate crosstalk between them. The first part of this review describes the human scaffolding proteins known to play a role in oncogenesis, pathways altered by them, and the impact on oncogenic processes. The second part provides information on the therapeutic potential of scaffolding proteins and future possibilities. The information on the explored and unexplored areas of the therapeutic potential of scaffolding proteins will be equally helpful for biologists and chemists.

Diversity of Short Linear Interaction Motifs in SARS-CoV-2 Nucleocapsid Protein

“…SLiMs have emerged as a ubiquitous modules in the organization of protein-protein interaction networks. For example, SLiMs designate substrates for post-translational modification including kinases and phosphatases, target cellular localization, and control docking to adaptors, assembly of signaling complexes, and recruitment of enzymes to multi-protein complexes (Manna et al, 2018;Mohapatra and Dixit, 2022;Peti and Page, 2013;Ragusa et al, 2010;Shi et al, 2023;Sorgeloos et al, 2022;Srivastava et al, 2023;Wang et al, 2016). The number of eukaryotic SLiM classes is in the hundreds and rapidly expanding, and it has been estimated there may be more than a hundred thousand of instances of such motifs in the human proteome (Davey et al, 2023;Kumar et al, 2022;Tompa et al, 2014).…”

Integrative analysis identifies AKAP8L as an immunological and prognostic biomarker of pan-cancer

“…In particular, for g protein-coupled receptors, AKAPs serve as a central hub in tissues for G protein-coupled receptors, allowing for the assembly of multiple protein kinases and phosphatases to create signal devices able to send signals, regulate and transport within cells [ 21 , 22 ]. It has been proved that AKAPs are pivotal for the initiation / progression of tumors and serve as potential targets of drug therapy [ 7 , 23 ]. For example, Zhang et al confirmed that AKAP4 was up-regulated in the tissues of non-small cell lung cancer, and the knockdown of AKAP4 inhibited tumor growth as well as epithelial-mesenchymal transformation, suggesting that AKAP4 might be a pivotal target in treating this disease [ 24 ].…”

Unraveling the dangerous duet between cancer cell plasticity and drug resistance

“…The MAPK pathway or mitogen‐activated protein kinase pathway [14] represents a cascade of protein kinases that are considered a key signaling pathway for the regulation of cellular and molecular functions like proliferation, apoptosis, differentiation and stress response [15]. The emergence of the MAPK pathway stems back 30 years ago [16] and is grouped into three families in mammals, namely, extracellular signal regulated kinases (ERKs), p38/SAKs, and c‐Jun N‐terminal kinases (JNKs) [17].…”