Myoferlin, a Membrane Protein with Emerging Oncogenic Roles

Abstract

Myoferlin (MYOF), initially identified in muscle cells, is a member of the Ferlin family involved in membrane fusion, membrane repair, and membrane trafficking. Dysfunction of this protein is associated with muscular dysfunction. Recently, a growing body of studies have identified MYOF as an oncogenic protein. It is overexpressed in a variety of human cancers and promotes tumorigenesis, tumor cell motility, proliferation, migration, epithelial to mesenchymal transition, angiogenesis as well as metastasis. Clinically, MYOF overexpression is associated with poor outcome in various cancers. It can serve as a prognostic marker of human malignant disease. MYOF drives the progression of cancer in various processes, including surface receptor transportation, endocytosis, exocytosis, intercellular communication, fit mitochondrial structure maintenance and cell metabolism. Depletion of MYOF demonstrates significant antitumor effects both in vitro and in vivo, suggesting that targeting MYOF may produce promising clinical benefits in the treatment of malignant disease. In the present article, we reviewed the physiological function of MYOF as well as its role in cancer, thus providing a general understanding for further exploration of this protein.

Figure 1

Schematic structure of MYOF. MYOF has seven C2 domains, a Ferlin A domain, a DysF domain as well as a single C-terminal transmembrane helix. C2-domains are responsible for Ca²⁺-dependent lipid binding and interacting with targeting proteins. FerA binds to phospholipids in a Ca²⁺ independent manner. DysF is possibly responsible for receptor-mediated endocytosis.

Figure 2

The role of MYOF in membrane trafficking. These trafficking processes have been identified in muscle fibers and other cells. They are also present in cancer cells. MYOF is present at the plasma and nucleus membrane as well as intracellular vesicle. It is involved in exocytosis, endocytosis, receptor internalization and recycling. For example, MYOF mediates endocytosis of transferrin by interacting with caveolin-1 (Cav-1) and dynamin-2 (Dyn-2). MYOF also directs vesicles containing VEGFR-2 to the plasma membrane to promote its surface expression and prevents it from proteasomal degradation. In addition, MYOF is responsible for internalization and recycling of receptors like IGF receptor. MYOF depletion redirects IGF receptor from recycling to a degradation pathway, which leads to mistrafficking of such receptor and disrupts IGF signaling. The secretion of lysosomal enzymes also requires MYOF, suggesting that this protein is widely involved in membrane trafficking.

Figure 3

Role of MYOF in EGFR-related pathway. MYOF gene is induced by MKL1/2 and SRF. MYOF directs p-EGFR to lysosome degradation and shuts off EGFR related signaling. Inhibition of MYOF leads to continuous phosphorylated EGFR, which further activates Ras/MEK/ERK and results in Oncogene-induced senescence.

Figure 4

The role of MYOF in IL-6R related pathway. Activity of MYOF is inhibited by EDH2 on cell membrane. Upon stimulation by IL-6, IL-6R phosphorylates STAT3, which interacts with MYOF and translocates to the nucleus. Phosphorylated STAT3 activates its target gene expression and promotes tumor progression.