Strength Through Unity: The Power of the Mega-Scaffold MACF1

Abstract

The tight coordination of diverse cytoskeleton elements is required to support several dynamic cellular processes involved in development and tissue homeostasis. The spectraplakin-family of proteins are composed of multiple domains that provide versatility to connect different components of the cytoskeleton, including the actin microfilaments, microtubules and intermediates filaments. Spectraplakins act as orchestrators of precise cytoskeletal dynamic events. In this review, we focus on the prototypical spectraplakin MACF1, a protein scaffold of more than 700 kDa that coordinates the crosstalk between actin microfilaments and microtubules to support cell-cell connections, cell polarity, vesicular transport, proliferation, and cell migration. We will review over two decades of research aimed at understanding the molecular, physiological and pathological roles of MACF1, with a focus on its roles in developmental and cancer. A deeper understanding of MACF1 is currently limited by technical challenges associated to the study of such a large protein and we discuss ideas to advance the field.

Keywords: ACF7; cancer; cytoskeleton; signaling; spectraplakin.

FIGURE 1

Mammalian MACF1 isoforms and interactors partners. Schematic representation of MACF1 isoforms. Direct interactors are highlighted. ABD, Actin-Binding-Domain; MTBD, Microtubules-Binding-Domain; GAR, Growth arrest-specific 2; GSR, Glycine-Serine-Arginine repeats; SxIP, Ser-x-Ile-Pro, Phospho-tyrosine in yellow and Phospho-serine in red.

FIGURE 2

Signaling by MACF1 in physiological and cancer context. (A) Upon Wnt stimulation, MACF1 is required for a proper translocation of the Axin/APC/GSK3β/β-catenin complex to the membrane. The subsequent degradation of Axin permits the translocation of β-catenin into the nucleus and the induction of migration, and proliferation -related genes. (B) Upon activation of the HER2 receptor by its ligand HRG, the complex Memo-RhoA-mDia localizes at the leading edge and inhibits GSK3β activity. This inhibition prevents APC phosphorylation and allows the recruitment of MACF1 that stabilizes MTs at the cell cortex.

FIGURE 3

Cell context-specific functions of MACF1. (A) At the neuromuscular junction, MACF1 promotes the stabilization of the AChR at the actin-rich postsynaptic membrane via its binding to Rapsyn and the recruitment of the EB1/MAP1b/Vinculin/βtubulin complex. (B) In ciliated cells, MACF1a connects the MTs with the basal body of the cilia via its interaction with Talpid3 and MKKs (not represented). This MT anchoring at the basal body is required for the docking of ciliary vesicles involved in cilium elongation. (C) In the intestinal epithelium, MACF1 participates in the maintenance of the intestinal barrier. MACF1 connects the MTs to ZO-1 positive tight junctions, affecting their dynamics by an unknown mechanism. (D) MACF1 is also involved in vesicular trafficking from the TGN through the plasma membrane via its interaction with GolginA4. For example, in hippocampal neurons, the complex of GTP-loaded Rab21, MACF1 and GolginA4 is required for the KIF5A-dependent transport along MT of TI-VAMP v-SNARE-tagged vesicles from the Golgi to neurite tips, which is essential for the axonal growth. (E) At the leading edge of migratory cells, MACF1 connects the growing MT tips to the FA to regulate FA turnover. MACF1 also induces the recruitment of the complex Elmo/DOCK that activates RAC1 to promote actin polymerization required for membrane protrusion.

FIGURE 4

Regulation of MACF1 by the E3 ubiquitin ligase HectD1. The control of MACF1 by HectD1 controls the transition between an epithelial and mesenchymal state. E3 ubiquitin ligase HectD1 mediates the formation of Lys-48-linked ubiquitin chains on MACF1 and targets it for proteasome-dependent degradation. Down regulation of HectD1 induces the stabilization of MACF1 and contributes to the acquisition of the mesenchymal phenotype.