RNA-binding protein IGF2BP2/IMP2 is required for laminin-β2 mRNA translation and is modulated by glucose concentration

Abstract

(LAMB2) is a critical component of the glomerular basement membrane as content of LAMB2 in part determines glomerular barrier permeability. Previously, we reported that high concentrations of glucose reduce expression of this laminin subunit at the translational level. The present studies were undertaken to further define systems that control Lamb2 translation and the effect of high glucose on those systems. Complementary studies were performed using in vitro differentiation of cultured podocytes and mesangial cells exposed to normal and elevated concentrations of glucose, and tissues from control and diabetic rats. Together, these studies provide evidence for regulation of Lamb2 translation by IMP2, an RNA binding protein that targets Lamb2 mRNA to the actin cytoskeleton. Expression of Imp2 itself is regulated by the transcription factor HMGA2, which in turn is regulated by the microRNA let-7b. Elevated concentrations of glucose increase let-7b, which reduces HMGA2 expression, in turn reducing IMP2 and LAMB2. Correlative changes in kidney tissues from control and streptozotocin-induced diabetic rats suggest these control mechanisms are operative in vivo and may contribute to proteinuria in diabetic nephropathy. To our knowledge, this is the first time that translation of Lamb2 mRNA has been linked to the actin cytoskeleton, as well as to specific RNA-binding proteins. These translational control points may provide new targets for therapy in proteinuric disorders such as diabetic nephropathy where LAMB2 levels are reduced.microRNA; diabetes LAMININS ARE HETEROTRIMERIC (␣␤␥), extracellular glycoproteins in glomerular (GBM) and other basement membranes (16). The laminin-␤2 (LAMB2) subunit is required for normal GBM structure and barrier function as human mutations causing loss of this protein lead to nephrotic syndrome and progressive kidney dysfunction (23,28,29,33). Mice deficient in LAMB2 die soon after birth with severe proteinuria and abnormal neuromuscular junctions (32, 33). Thus, LAMB2 is a key subunit in the laminin family, providing critical functions in kidney and other tissues (40).Mechanisms controlling expression of the Lamb2 gene as well as LAMB2 protein production, secretion, and degradation are not well-understood (17). We previously demonstrated that LAMB2 is not expressed in developing glomeruli of hyperglycemic animals, and it is reduced in kidneys of rats with streptozotocin-induced diabetes (2), as a result of glucosemediated impairment of Lamb2 mRNA translation (39). Also, loss of LAMB2 results in impaired migratory responses of mesangial cells (MC), which may limit repair in the face mesangiolysis, a prominent feature of diabetic nephropathy (DN) (39). Glucose-mediated reductions in LAMB2 content in GBM may also contribute to microalbuminuria in DN (30).In this report, we demonstrate that the RNA-binding protein (RNA-BP) IMP2 is required for LAMB2 translation, as 1) Lamb2 mRNA binds specifically to IMP2 and associates with actin during translation, 2) LAMB2 protein production is reduced if ...

Oncogenic NRAS, Required for Pathogenesis of Embryonic Rhabdomyosarcoma, Relies upon the HMGA2–IGF2BP2 Pathway

“…IGF2BP family members have been shown to perturb stability and translation efficiency of the mRNAs they bind to (16, 20–22). Therefore, we first tried to identify mRNAs bound by IGF2BP2 in ERMS cells.…”

MicroRNA Let‐7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2

“…We focus on the IGF2BP2 because some recent reports have shown that HMGA2 has a relationship with IGF2BP2 and the axis of HMGA2‐IGF2BP2 complex has the functions as a critical regulator of satellite cell activation during skeletal muscle development . Let‐7b preferentially regulates or modulates transcription factor HMGA2, which is required to transcribe IMP2 . Interestingly, the lower expression of IGF2BP2 was found in the skin of transgenic mice when compared with wild‐type mice, which implicated that let‐7b might relate to IGF2BP2.…”

Laminins 411 and 421 differentially promote tumor cell migration via α6β1 integrin and MCAM (CD146)

“…Notably, hypoxia, which often occurs in tumors and triggers EMT via Notch-1 signaling (Christofori, 2006;Sahlgren et al, 2008), induces expression of the laminin β2 chain in tumor cells (Bao et al, 2006), and MCAM is a target of Notch1 signaling (Pinnix et al, 2009). In addition, RNA-binding protein IGFBP2/IMP2, which is required for laminin β2 mRNA translation, is induced by HMGA2, a transcription factor expressed in tumor cells at the invasive front and an inducer of EMT and tumor metastasis (Miyazawa et al, 2004;Thuault et al, 2006;Schaeffer et al, 2012;Morishita et al, 2013). TGFβ, a classical elicitor of EMT via HMGA2 (Thuault et al, 2006;Heldin et al, 2012), can induce expression of both LMα4 chain and MCAM in cells (Gaspar et al, 2007;Wang and Yan, 2013).…”