The Actin Binding Protein Plastin-3 Is Involved in the Pathogenesis of Acute Myeloid Leukemia

Velthaus, Arne; Cornils, Kerstin; Hennigs, Jan K.; Grüb, Saskia; Stamm, Hauke; Wicklein, Daniel; Bokemeyer, Carsten; Heuser, Michael; Windhorst, Sabine; Fiedler, Walter; Wellbrock, Jasmin

doi:10.3390/cancers11111663

Cited by 10 publications

(5 citation statements)

References 38 publications

(41 reference statements)

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“…Elevated PLS3 expression is a negative prognostic marker for acute myeloid leukemia (AML), the most common acute leukemia in adults, while knockdown of PLS3 increases survival in vivo [95]. In Sézary Syndrome (SS), an aggressive, rare form of cutaneous T-cell lymphomas (CTCL), circulating CD4 + T-cells show increased expression of PLS3, TWIST1 and GATA6 compared to normal CD4 + T-cells [96,97].…”

Section: Malignancies Of the Hematopoietic And Lymphatic Systemmentioning

confidence: 99%

Plastin 3 in health and disease: a matter of balance

Wolff

Strathmann

Müller

et al. 2021

Cell. Mol. Life Sci.

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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.

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Section: Malignancies Of the Hematopoietic And Lymphatic Systemmentioning

confidence: 99%

Plastin 3 in health and disease: a matter of balance

Wolff

Strathmann

Müller

et al. 2021

Cell. Mol. Life Sci.

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“…Previous findings suggest that the majority of the OI-linked PLS3 pathogenic variants are either loss-of-function changes (nonsense or frameshift varaints) which rarely result in translated protein products due to nonsense-mediated mRNA decay [ 16 , 23 ]. Separately, a rare single nucleotide polymorphism of the PLS3 gene was reported in association with osteoporosis in postmenopausal women [ 24 ]. The current identified X-linked PLS3 actin bundling-deficient mutation (L478P) that produces a full-length protein disables actin-binding in the ABD2 and thus prevents F-actin bundling.…”

Section: Discussionmentioning

confidence: 99%

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

Brlek

Antičević

Molnar³

et al. 2021

Genes

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Osteogenesis imperfecta (OI) represents a complex spectrum of genetic bone diseases that occur primarily due to mutations and deletions of the COL1A1 and COL1A2 genes. Recent molecular studies of the network of signaling pathways have contributed to a better understanding of bone remodeling and the pathogenesis of OI caused by mutations in many other genes associated with normal bone mineralization. In this paper, a case of a rare X-linked variant of OI with a change in the gene encoding plastin 3—a protein important for the regulation of the actin cytoskeleton, is presented. A 16-year-old patient developed ten bone fractures caused by minor trauma or injury, including a compression fracture of the second lumbar vertebra during his lifetime. Next-generation sequencing analysis did not show pathologically relevant deviations in the COL1A1 and COL1A2 genes. Targeted gene analyses (Skeletal disorder panel) of the patient, his father, mother and sister were then performed, detecting variants of uncertain significance (VUS) for genes PLS3, FN1 and COL11A2. A variant in the PLS3 gene were identified in the patient, his mother and sister. Since the PLS3 gene is located on the X chromosome, the mother and sister showed no signs of the disease. Although the variant in the PLS3 gene (c.685G>A (p.Gly229Arg)) has not yet been described in the literature, nor is its pathogenicity known, clinical findings combined with genetic testing showed that this variant may explain the cause of X-linked OI in our patient. This rare case of the PLS3 variant of X-linked OI might point to a novel target for personalized therapy in patients with this severe disease.

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“…In a zebrafish SMA model, T- and L-, but not I-plastin, decreased the phenotype severity [ 161 ], emphasizing isoform specialization, but also their partial redundancy. While L-plastin is associated with solid tumors, ectopic expression of T-plastin is a marker and indicator of poor prognosis of blood malignancies [ 162 , 163 ] and pancreatic cancers [ 164 , 165 ]. The role of T-plastin in various cell functions has been recently reviewed [ 11 ].…”

Section: Actin-bundling Proteinsmentioning

confidence: 99%

Actin Bundles Dynamics and Architecture

2023

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Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into bundles or regulate their morphology is being identified in cells. With recent advances in high-resolution microscopy and imaging techniques, the complex process of bundles formation and the multiple forms of physiological bundles are beginning to be better understood. Here, we review the physiochemical and biological properties of four families of highly conserved and abundant actin-bundling proteins, namely, α-actinin, fimbrin/plastin, fascin, and espin. We describe the similarities and differences between these proteins, their role in the formation of physiological actin bundles, and their properties—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundles formation, which are known from the available information on the activity of the key actin partners involved in this process.

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The Actin Binding Protein Plastin-3 Is Involved in the Pathogenesis of Acute Myeloid Leukemia

Cited by 10 publications

References 38 publications

Plastin 3 in health and disease: a matter of balance

Plastin 3 in health and disease: a matter of balance

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

Actin Bundles Dynamics and Architecture

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