Plastin 3 in health and disease: a matter of balance

Abstract

For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.

Identification of Tumor-Suppressive miR-30e-3p Targets: Involvement of SERPINE1 in the Molecular Pathogenesis of Head and Neck Squamous Cell Carcinoma

“…For example, Plastin-3 ( PLS3 ) is an actin-bundling protein that contributes to cofilin-mediated actin polymerization [ 37 ]. The aberrant expression of PLS3 was reported in a wide range of cancers, and its expression is closely associated with the EMT-induced malignant phenotypes of cancers [ 38 ]. A previous study showed that the expression of PLS3 by circulating tumor cells was a marker in metastatic colorectal cancer [ 39 ].…”

Identification of a novel splicing mutation and genotype–phenotype correlations in rare PLS3-related childhood-onset osteoporosis

“…Still, bisphosphonates should be prescribed simultaneously. There is a huge variation of osteoporotic phenotype among heterozygous women, and heterozygous female patients are generally less severely affected compared with hemizygous males [ 4 ]. The phenomenon can be explained by the variability in X inactivation, which is a process by which one of the copies of the X chromosome is inactivated in therian female mammals [ 9 ].…”

“…In 2013, van Dijk et al firstly identified plastin3 (PLS3) gene as a monogenetic cause of childhood-onset osteoporosis using X-linked whole-exome sequencing in 5 unrelated families [ 3 ]. Subsequently, more novel mutation sites in PLS3 gene responsible for X-linked osteoporosis were reported by other researchers [ 4 ]. PLS3, located on chromosome Xq23, encodes protein plastin 3 which is ubiquitously expressed in solid tissues and considered to be involved in cytoskeleton remodeling [ 5 ].…”

“…It is widely accepted that deficiency of PLS3 caused by pathogenic mutations will lead to early-onset osteoporosis. However, the genetic spectrum, phenotypic variability and treatment approaches of PLS3 induced osteoporosis are not fully understood as hampered by its extremely low incidence [ 4 ]. Moreover, the association between PLS3 levels and osteoporosis in individuals without pathogenic mutations in PLS3 needs to be determined.…”

X-Linked Osteogenesis Imperfecta Possibly Caused by a Novel Variant in PLS3

“…The clinical presentation in hemizygous men matched the presentation of classical OI and was variable in heterozygous women [ 14 ]. The main role of PLS3 is in F-actin-binding, which consequently suggests that PLS3 participates in all processes dependent on F-actin dynamics, such as cell motility, cell division, focal adhesion, endocytosis, neurotransmission, vesicle trafficking, axonal local translation, and intracellular calcium PLS3-dependent processes [ 15 , 16 ]. Plastins are proteins with a single polypeptide chain composed of two tandem repeats of actin-binding domains (ABD1 and ABD2).…”