Pleckstrin-2 is essential for erythropoiesis in β-thalassemic mice, reducing apoptosis and enhancing enucleation

Abstract

Erythropoiesis involves complex interrelated molecular signals influencing cell survival, differentiation, and enucleation. Diseases associated with ineffective erythropoiesis, such as β-thalassemias, exhibit erythroid expansion and defective enucleation. Clear mechanistic determinants of what make erythropoiesis effective are lacking. We previously demonstrated that exogenous transferrin ameliorates ineffective erythropoiesis in β-thalassemic mice. In the current work, we utilize transferrin treatment to elucidate a molecular signature of ineffective erythropoiesis in β-thalassemia. We hypothesize that compensatory mechanisms are required in β-thalassemic erythropoiesis to prevent apoptosis and enhance enucleation. We identify pleckstrin-2—a STAT5-dependent lipid binding protein downstream of erythropoietin—as an important regulatory node. We demonstrate that partial loss of pleckstrin-2 leads to worsening ineffective erythropoiesis and pleckstrin-2 knockout leads to embryonic lethality in β-thalassemic mice. In addition, the membrane-associated active form of pleckstrin-2 occurs at an earlier stage during β-thalassemic erythropoiesis. Furthermore, membrane-associated activated pleckstrin-2 decreases cofilin mitochondrial localization in β-thalassemic erythroblasts and pleckstrin-2 knockdown in vitro induces cofilin-mediated apoptosis in β-thalassemic erythroblasts. Lastly, pleckstrin-2 enhances enucleation by interacting with and activating RacGTPases in β-thalassemic erythroblasts. This data elucidates the important compensatory role of pleckstrin-2 in β-thalassemia and provides support for the development of targeted therapeutics in diseases of ineffective erythropoiesis.

Iron Chelation Improves Ineffective Erythropoiesis and Iron Overload in Myelodysplastic Syndrome Mice

“…However, whether increased ROS resulting in apoptosis as the cause of ineffective erythropoiesis has never been definitely confirmed. We and others previously demonstrate that EPO downstream mechanisms are potent anti-apoptotic compensatory mechanisms and that reversal of apoptosis does not ameliorate ineffective erythropoiesis in β-thalassemia [76,77]. Our current results demonstrate borderline increased erythroblast apoptosis while ROS is significantly enhanced in MDS mice and no change in apoptosis while ROS is significantly decreased in DFP-treated MDS mice.…”

PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c‐Myc‐mediated positive feedback loop

“…PLEK2 binds to membrane‐associated phosphatidylinositol produced by phosphatidylinositol 3‐kinase, which subsequently regulates actin cytoskeleton organization and cell spreading [ 6 ]. Although aberrant expression of PLEK2 has been shown to play a critical role in regulating many important biological processes such as inflammation, erythropoiesis and tumorigenesis [ 7 , 8 , 9 ], its underlying cellular and molecular mechanisms remain poorly understood. PLEK2 was reported to be highly expressed in several malignancies, including non‐small cell lung cancer [ 10 ], gallbladder cancer [ 11 ] and gastric cancer [ 12 ], while low PLEK2 mRNA levels were observed in multiple myeloma bone marrow progenitor cells [ 13 ] and prostate cancer [ 14 ].…”

Pleckstrin-2 as a Prognostic Factor and Mediator of Gastric Cancer Progression

“…The DEP domain is in the center, and the two PH domains are in the amino- and carboxyl-terminals, which are important for PLEK2 colocalization with the actin cytoskeleton at the immune synapse and integrin clusters and involve a broad range of cellular functions [ 10 – 13 ]. Previous studies have shown that PLEK2 regulates actin dynamics and cofilin's mitochondrial localization during erythropoiesis [ 14 , 15 ]. PLEK2 induces lamellipodia formation depending on its DEP domain.…”