Microtubule-Actin Crosslinking Factor 1 and Plakins as Therapeutic Drug Targets

Abstract

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the three major filaments that comprise the cytoskeleton. Plakins have been found to be involved in disorders and diseases of the skin, heart, nervous system, and cancer that are attributed to autoimmune responses and genetic alterations of these macromolecules. Despite their role and involvement across a spectrum of several diseases, there are no current drugs or pharmacological agents that specifically target the members of this protein family. On the contrary, microtubules have traditionally been targeted by microtubule inhibiting agents, used for the treatment of diseases such as cancer, in spite of the deleterious toxicities associated with their clinical utility. The Research Collaboratory for Structural Bioinformatics (RCSB) was used here to identify therapeutic drugs targeting the plakin proteins, particularly the spectraplakins MACF1 and BPAG1, which contain microtubule-binding domains. RCSB analysis revealed that plakin proteins had 329 ligands, of which more than 50% were MACF1 and BPAG1 ligands and 10 were documented, clinically or experimentally, to have several therapeutic applications as anticancer, anti-inflammatory, and antibiotic agents.

Cellular Interactome Dynamics during Paclitaxel Treatment

“…K2209 of MACF1 was also cross-linked to two sites in the middle domain of HS90B. Although not a direct target of PTX, MACF1 has been shown to be indirectly affected and differentially responsive to MT-targeting drugs (Quick, 2018). MACF1 is associated with several diseases, including cancer, suggesting it could be a useful therapeutic target for future drug development (Afghani et al, 2017; Miao et al, 2017; Quick, 2018).…”

“…Although not a direct target of PTX, MACF1 has been shown to be indirectly affected and differentially responsive to MT-targeting drugs (Quick, 2018). MACF1 is associated with several diseases, including cancer, suggesting it could be a useful therapeutic target for future drug development (Afghani et al, 2017; Miao et al, 2017; Quick, 2018). AHNK2 is an oncogenic protein and prognostic marker in several carcinomas, including pancreatic ductal adenocarcinoma (PDAC), a highly aggressive and malignant disease that is currently the fourth-leading cause of cancer deaths worldwide (Bhasin et al, 2016; Garrido-Laguna and Hidalgo, 2015; Klett et al, 2018; Lu etal., 2017; Wang etal., 2017).…”

Mammalian Plakins, Giant Cytolinkers: Versatile Biological Functions and Roles in Cancer

“…As the downregulation of desmoplakin has been found in OSCC [ 133 ] ( Table 2 ), the finding of Lorch et al suggests desmoplakin as a potential target for cancer therapy. More recently, Quick, by using the Research Collaboratory for Structural Bioinformatics (RCSB) protein data bank, has identified several anticancer drugs that interact with BPAG1, MACF1, and plectin [ 143 ]. Ibrutinib is one common ligand for both BPAG1 and MACF1, and is used clinically for the treatment of lymphoma and leukemia [ 144 , 145 ].…”

Comorbidities and Treatment Strategies in Bullous Pemphigoid: An Appraisal of the Existing Litterature

“…The association between BP and neurodegenerative diseases is well-described ( 11 , 12 ). There is evidence that having a neurodegenerative disease increases the risk for developing BP and that patients with neurodegenerative diseases have a higher standardized mortality rate.…”

“…A new publication by Quick et al elucidates BP antigens as potential targets in future therapy of patients with BP ( 11 ).…”