Microtubule actin crosslinking factor 1, a brain tumor oncoprotein (Review)

Abstract

Microtubule actin crosslinking factor 1 (MACF1), is a cytoskeletal protein that functions as a crosslinker between microtubules and actin filaments, with early studies expanding the role of this spectraplakin protein to the central nervous system and Wnt signaling. In the early 2000's, genetic alterations of MACF1 were identified in several cancers suggesting that this cytoskeletal crosslinker was involved in tumor development and progression, while preclinical studies provided evidence that MACF1 is a potential diagnostic and prognostic biomarker and therapeutic target in glioblastomas, a central nervous system cancer derived from astrocytes and neural progenitor stem cells. Furthermore, investigations in glioblastomas demonstrated that genetic inhibitory targeting of this spectraplakin protein alone and in combination with DNA damaging agents had synergistic antitumorigenic effects. The established role of MACF1 in Wnt signaling, a known mechanistic driver of central nervous system development and pro-tumorigenic cell behavior in glioblastomas, provide a premise for addressing the potential of this spectraplakin protein as a novel oncoprotein in cancers with origins in the nervous system. The present review provides a summary of the role and function of MACF1 in the central nervous system, Wnt signaling and cancer development, specifically as an oncoprotein that underlie the transformation and oncogenic properties of glioblastomas.

Keywords: MACF1; Wnt; astrocytes; cancer; glioblastoma; nervous system; oncoprotein; tumor development.

Figure 1

MACF1 supports axon growth, nervous system development and cortex organization. (A) Wild-type MACF1 maintains axon and growth cone extension via crosslinking stabilization of microtubules and actin filaments that supports cellular organization of cortical layers in the cerebral cortex of the brain. (B) Deletion of MACF1 disrupts crosslinking stabilization and interaction of microtubules and actin filaments leading to disorganization of cerebral cortex cortical layers. (purple-pyramidal neurons; green-stellate neurons). The figure was created using bioRender (https://www.biorender.com/). MACF1, microtubule actin crosslinking factor.

Figure 2

MACF1 promotes proliferative growth, transformation and cell migration. Schematic of MACF1 genetic alterations leading to astrocyte transformation and glioblastoma development. The figure was created using bioRender (https://www.biorender.com/). MACF1, microtubule actin crosslinking factor.

Figure 3

MACF1 is an effector mediator of Wnt and mTOR signaling. MACF1 has been described as a component of the Wnt signaling complex (GSK3β, axin, APC and beta-catenin) and assists with the translocation of these signaling mediators to the LRP receptor and activation of this signaling cascade. Subsequently, beta-catenin is released to facilitate its transcriptional activation function via interaction with TCF/LCF. Suppression of MACF1 has been demonstrated to reduce axin, beta-catenin,and s6-ribosomal protein expression levels and attributed to reducing glioblastoma cell proliferation and migration. The figure was created using bioRender (https://www.biorender.com/). MACF1, microtubule actin crosslinking factor; GSK-3, glycogen synthase kinase-3; APC, adenomatous polyposis coli; LRP, low-density lipoprotein receptor-related protein; TCF/LEF, T cell factor, lymphocyte enhancer factor-1.