ORCID Profile
0000-0002-9414-6558
Current Organisation
Monash University
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Protein Trafficking | Biochemistry and Cell Biology | Receptors and Membrane Biology | Signal Transduction
Publisher: Elsevier BV
Date: 05-2014
Publisher: EMBO
Date: 15-08-2022
Abstract: Autophagy depends on the repopulation of lysosomes to degrade intracellular components and recycle nutrients. How cells co‐ordinate lysosome repopulation during basal autophagy, which occurs constitutively under nutrient‐rich conditions, is unknown. Here, we identify an endosome‐dependent phosphoinositide pathway that links PI3Kα signaling to lysosome repopulation during basal autophagy. We show that PI3Kα‐derived PI(3)P generated by INPP4B on late endosomes was required for basal but not starvation‐induced autophagic degradation. PI(3)P signals were maintained as late endosomes matured into endolysosomes, and served as the substrate for the 5‐kinase, PIKfyve, to generate PI(3,5)P 2 . The SNX‐BAR protein, SNX2, was recruited to endolysosomes by PI(3,5)P 2 and promoted lysosome reformation. Inhibition of INPP4B/PIKfyve‐dependent lysosome reformation reduced autophagic clearance of protein aggregates during proteotoxic stress leading to increased cytotoxicity. Therefore under nutrient‐rich conditions, PI3Kα, INPP4B, and PIKfyve sequentially contribute to basal autophagic degradation and protection from proteotoxic stress via PI(3,5)P 2 ‐dependent lysosome reformation from endolysosomes. These findings reveal that endosome maturation couples PI3Kα signaling to lysosome reformation during basal autophagy.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-12-2021
Abstract: Exercise-induced ROS mediates antioxidant defense to attenuate oxidative damage and insulin resistance in aging and obesity.
Publisher: American Physiological Society
Date: 12-2003
DOI: 10.1152/AJPCELL.00207.2003
Abstract: Skeletal muscle LIM protein 1 (SLIM1/FHL1) contains four and a half LIM domains and is highly expressed in skeletal and cardiac muscle. Elevated SLIM1 mRNA expression has been associated with postnatal skeletal muscle growth and stretch-induced muscle hypertrophy in mice. Conversely, SLIM1 mRNA levels decrease during muscle atrophy. Together, these observations suggest a link between skeletal muscle growth and increased SLIM1 expression. However, the precise function of SLIM1 in skeletal muscle, specifically the role of SLIM1 during skeletal muscle differentiation, is not known. This study investigated the effect of increased SLIM1 expression during skeletal muscle differentiation. Western blot analysis showed an initial decrease followed by an increase in SLIM1 expression during differentiation. Overexpression of SLIM1 in Sol8 or C 2 C 12 skeletal muscle cell lines, at levels observed during hypertrophy, induced distinct effects in differentiating myocytes and undifferentiated reserve cells, which were distinguished by differential staining for two markers of differentiation, MyoD and myogenin. In differentiating skeletal myocytes, SLIM1 overexpression induced hyperelongation, which, by either plating cells on poly-l-lysine or using a series of peptide blockade experiments, was shown to be specifically dependent on ligand binding to the α 5 β 1 -integrin, whereas in reserve cells, SLIM1 overexpression induced the formation of multiple cytoplasmic protrusions (branching), which was also integrin mediated. These results suggest that SLIM1 may play an important role during the early stages of skeletal muscle differentiation, specifically in α 5 β 1 -integrin-mediated signaling pathways.
Publisher: Elsevier BV
Date: 03-2200
Publisher: American Association for Cancer Research (AACR)
Date: 13-08-2013
DOI: 10.1158/0008-5472.CAN-12-4520
Abstract: It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR–filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer. Cancer Res 73(16) 5066–79. ©2013 AACR.
Publisher: Oxford University Press (OUP)
Date: 18-10-2020
DOI: 10.1093/HMG/DDZ232
Abstract: Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3- kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD, however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome lification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.
Publisher: Elsevier BV
Date: 06-2003
Publisher: Elsevier BV
Date: 03-2003
Publisher: Rockefeller University Press
Date: 15-12-2008
Abstract: Regulators of skeletal muscle mass are of interest, given the morbidity and mortality of muscle atrophy and myopathy. Four-and-a-half LIM protein 1 (FHL1) is mutated in several human myopathies, including reducing-body myopathy (RBM). The normal function of FHL1 in muscle and how it causes myopathy remains unknown. We find that FHL1 transgenic expression in mouse skeletal muscle promotes hypertrophy and an oxidative fiber-type switch, leading to increased whole-body strength and fatigue resistance. Additionally, FHL1 overexpression enhances myoblast fusion, resulting in hypertrophic myotubes in C2C12 cells, (a phenotype rescued by calcineurin inhibition). In FHL1-RBM C2C12 cells, there are no hypertrophic myotubes. FHL1 binds with the calcineurin-regulated transcription factor NFATc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1), enhancing NFATc1 transcriptional activity. Mutant RBM-FHL1 forms aggregate bodies in C2C12 cells, sequestering NFATc1 and resulting in reduced NFAT nuclear translocation and transcriptional activity. NFATc1 also colocalizes with mutant FHL1 to reducing bodies in RBM-afflicted skeletal muscle. Therefore, via NFATc1 signaling regulation, FHL1 appears to modulate muscle mass and strength enhancement.
Publisher: Elsevier BV
Date: 04-1999
Abstract: LIM proteins perform critical roles in development and tissue differentiation. The skeletal muscle LIM protein 1 (SLIM1) comprises four and a half LIM domains. Northern blot analysis demonstrated high level expression of SLIM1 mRNA in adult human skeletal muscle with intermediate expression in adult heart and lower expression in other tissues. Western blot analysis using specific affinity-purified anti-SLIM1 antipeptide antibodies demonstrated a 32 kDa polypeptide in the aorta and atria of rabbit heart, but not in vena cava, interventricular septum or ventricular muscle. SLIM1 was also demonstrated in rabbit skeletal muscle. In situ hybridization of whole mouse embryos confirmed the cardiac expression of SLIM1 was restricted to the cardiac outflow tract from embryonic day 8.5-11. No expression was seen in atrial or ventricular muscle. SLIM1 mRNA was also demonstrated in the hindbrain, neural tube and somites. The localized expression of SLIM1 to the outflow tract of the embryonic heart implies an important role for the protein in the development of this region and possibly in congenital heart anomalies involving the separation and formation of the aortic and pulmonary trunks.
Publisher: Informa UK Limited
Date: 21-11-2022
DOI: 10.1080/15548627.2022.2128019
Abstract: Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded. Autophagy cannot proceed without the sufficient generation of lysosomes, and this can be achieved via their de novo biogenesis. Alternatively, during autophagic lysosome reformation (ALR), lysosomes are generated via the recycling of autolysosome membranes. During this process, autolysosomes undergo significant membrane remodeling and scission to generate membrane fragments, that mature into functional lysosomes. By utilizing membranes already formed during autophagy, this facilitates an efficient pathway for re-deriving lysosomes, particularly under conditions of prolonged autophagic flux. ALR dysfunction is emerging as an important disease mechanism including for neurodegenerative disorders such as hereditary spastic paraplegia and Parkinson disease, neuropathies including Charcot-Marie-Tooth disease, lysosome storage disorders, muscular dystrophy, metabolic syndrome, and inflammatory and liver disorders. Here, we provide a comprehensive review of ALR, including an overview of its dynamic spatiotemporal regulation by MTOR and phosphoinositides, and the role ALR dysfunction plays in many diseases.
Publisher: Informa UK Limited
Date: 26-09-2022
DOI: 10.1080/15548627.2022.2124499
Abstract: Macroautophagy/autophagy occurs basally under nutrient-rich conditions in most mammalian cells, contributing to protein and organelle quality control, and protection against aging and neurodegeneration. During autophagy, lysosomes are heavily utilized via their fusion with autophagosomes and must be repopulated to maintain autophagic degradative capacity. During starvation-induced autophagy, lysosomes are generated via
Publisher: Informa UK Limited
Date: 20-04-2021
Publisher: Wiley
Date: 06-2001
DOI: 10.1080/152165401753366113
Abstract: LIM domains are double zinc-finger motifs that mediate protein interactions between transcription factors, cytoskeletal and signaling proteins. This review outlines the protein interactions mediated by LIM domains with signaling proteins including tyrosine and serine/threonine kinases and phosphatases.
Publisher: The Company of Biologists
Date: 2014
DOI: 10.1242/JCS.140905
Abstract: FHL1 mutations cause several clinically heterogeneous myopathies including Reducing Body Myopathy (RBM), Scapuloperoneal Myopathy (SPM) and X-Linked Myopathy with Postural Muscle Atrophy (XMPMA). The molecular mechanisms underlying the pathogenesis of FHL1 myopathies are unknown. Protein aggregates designated “Reducing Bodies” (RBs) containing mutant FHL1 are detected in RBM muscle but not several other FHL1 myopathies. Here RBM, SPM and XMPMA FHL1 mutants were expressed in C2C12 cells and showed equivalent protein expression to wild-type FHL1 and formed aggregates positive for the RB stain Menadione-NBT, analogous to RBM muscle aggregates. However HCM and EDMD FHL1 mutants generally exhibited reduced expression. Wild-type FHL1 promotes myoblast differentiation however RBM, SPM and XMPMA mutations impaired differentiation, consistent with loss-of-normal function. Furthermore, SPM and XMPMA mutants retarded myotube formation relative to vector control consistent with a dominant-negative/toxic function. Mutant FHL1 myotube formation was partially rescued by expression of the FHL1-binding partner constitutively-active NFATc1. This is the first study to show FHL1 mutations identified in several clinically distinct myopathies lead to similar protein aggregation and impaired myotube formation suggesting a common pathogenic mechanism despite heterogenous clinical features.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.NMD.2011.01.001
Abstract: Mutations in the four and a half LIM protein 1 (FHL1) gene were recently identified as the cause of four distinct skeletal muscle diseases. Since the initial report outlining the first fhl1 mutation in 2008, over 25 different mutations have been identified in patients with reducing body myopathy, X-linked myopathy characterized by postural muscle atrophy, scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. Reducing body myopathy was first described four decades ago, its underlying genetic cause was unknown until the discovery of fhl1 mutations. X-linked myopathy characterized by postural muscle atrophy is a novel disease where fhl1 mutations are the only cause. This review will profile each of the FHL1, with a comprehensive analysis of mutations, a comparison of the clinical and histopathological features and will present several hypotheses for the possible disease mechanism(s).
Publisher: Oxford University Press (OUP)
Date: 20-04-2012
DOI: 10.1093/HMG/DDS157
Abstract: Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Physiological Society
Date: 03-2003
DOI: 10.1152/AJPCELL.00370.2002
Abstract: The skeletal muscle LIM protein 1 (SLIM1) is highly expressed in skeletal and cardiac muscle, and its expression is downregulated significantly in dilated human cardiomyopathy. However, the function of SLIM1 is unknown. In this study, we investigated the intracellular localization of SLIM1. Endogenous and recombinant SLIM1 localized to the nucleus, stress fibers, and focal adhesions in skeletal myoblasts plated on fibronectin, collagen, or laminin. However, after inhibition of integrin signaling either by plating on poly-l-lysine or by soluble RGD peptide, SLIM1 localized diffusely in the cytosol, with decreased nuclear expression. Disruption of the actin cytoskeleton by cytochalasin D did not inhibit nuclear localization of SLIM1 in integrin-activated cells. Green fluorescent protein-tagged SLIM1 shuttled in the nucleus of untransfected NIH 3T3 cells, in a heterokaryon fusion assay. Overexpression of SLIM1 in Sol8 myoblasts inhibited cell adhesion and promoted cell spreading and migration. These studies show SLIM1 localizes in an integrin-dependent manner to the nucleus and focal adhesions where it functions downstream of integrin activation to promote cell spreading and migration.
Publisher: Elsevier BV
Date: 09-2009
Publisher: American Society for Clinical Investigation
Date: 02-2008
DOI: 10.1172/JCI34450
Publisher: Oxford University Press (OUP)
Date: 18-09-2013
DOI: 10.1093/HMG/DDT449
Abstract: Utrophin is a potential therapeutic target for the fatal muscle disease, Duchenne muscular dystrophy (DMD). In adult skeletal muscle, utrophin is restricted to the neuromuscular and myotendinous junctions and can compensate for dystrophin loss in mdx mice, a mouse model of DMD, but requires sarcolemmal localization. NFATc1-mediated transcription regulates utrophin expression and the LIM protein, FHL1 which promotes muscle hypertrophy, is a transcriptional activator of NFATc1. By generating mdx/FHL1-transgenic mice, we demonstrate that FHL1 potentiates NFATc1 activation of utrophin to ameliorate the dystrophic pathology. Transgenic FHL1 expression increased sarcolemmal membrane stability, reduced muscle degeneration, decreased inflammation and conferred protection from contraction-induced injury in mdx mice. Significantly, FHL1 expression also reduced progressive muscle degeneration and fibrosis in the diaphragm of aged mdx mice. FHL1 enhanced NFATc1 activation of the utrophin promoter and increased sarcolemmal expression of utrophin in muscles of mdx mice, directing the assembly of a substitute utrophin-glycoprotein complex, and revealing a novel FHL1-NFATc1-utrophin signaling axis that can functionally compensate for dystrophin.
Publisher: SAGE Publications
Date: 22-09-2014
Abstract: FHL1 gene mutations are associated with reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, Emery-Dreifuss muscular dystrophy, and isolated hypertrophic cardiomyopathy. We describe a boy with a family history consistent with X-linked distal myopathy/cardiomyopathy. The boy first presented at age 14 years and was found to have distal wasting and weakness. Echocardiogram revealed hypertrophic cardiomyopathy. Muscle biopsy showed a vacuolar pathology with no reducing bodies. Sequencing of FHL1 revealed a novel hemizygous c.764G C missense mutation in exon 8. This is the first report of a predominantly distal myopathy with hypertrophic cardiomyopathy occurring secondary to an FHL1 mutation.
Publisher: The Company of Biologists
Date: 15-04-2007
DOI: 10.1242/JCS.004739
Abstract: MyoD initiates muscle differentiation and promotes skeletal myogenesis by regulating temporal gene expression. MyoD-interacting proteins induce regulatory effects, and the identification of new MyoD-binding partners may provide mechanistic insights into the regulation of gene expression during myogenesis. FHL3 is one of three members of the FHL protein family that are expressed in skeletal muscle, but its function in myogenesis is unknown. Overexpression of human FHL3 in mouse C2C12 cells retarded myotube formation and decreased the expression of muscle-specific regulatory genes such as myogenin but not MyoD. By contrast, short interfering RNA (siRNA)-mediated FHL3 protein knockdown enhanced myoblast differentiation associated with increased myogenin, but not MyoD protein expression, early during differentiation. We demonstrate that FHL3 is a MyoD-associated protein by direct binding assays, colocalisation in the nucleus of myoblasts and GST pull-down studies. Moreover, we determined that FHL3 interacts with MyoD, functioning as its potent negative co-transcriptional regulator. Ectopic expression of FHL3 in myoblasts impaired MyoD-mediated transcriptional activity and muscle gene expression. By contrast, siRNA-mediated FHL3 knockdown enhanced MyoD transcriptional activity in a dose-dependent manner. These findings reveal that FHL3 association with MyoD may contribute to the regulation of MyoD-dependent transcription of muscle genes and thereby myogenesis.
Publisher: Oxford University Press (OUP)
Date: 24-01-2008
DOI: 10.1093/CVR/CVN038
Abstract: Protein-protein interactions are critical for the normal membrane trafficking, localization, and function of voltage-gated ion channels. In human heart, the Shaker-related voltage-gated K(+) channel KCNA5 alpha-subunit forms the major basis of an atrial-specific, ultra-rapid delayed rectifier K(+) current, I(Kur). We sought to identify proteins that interact with KCNA5 in human atrium and investigate their role in the I(Kur) complex. Using a glutathione-S-transferase (GST)-KCNA5 C-terminal fusion protein and mass spectrometry-based methods, the scaffolding protein four and a half LIM (for Lin-11, Isl-1, and Mec3) protein 1 (FHL1) was identified as a potential protein partner for KCNA5. Immunoprecipitation experiments confirmed a physical interaction of FHL1 with the K(+) channel complex in human atrium, as well as in Chinese hamster ovary (CHO) cells transfected with both KCNA5 and FHL1. In cotransfected cells, confocal microscopy demonstrated areas of colocalization after immunolabelling both proteins. To investigate the functional effects of this interaction, K(+) currents were recorded in CHO cells transfected with KCNA5 in the absence and presence of FHL1 coexpression. With coexpression of FHL1, K(+) current density was markedly increased, compared with cells expressing KCNA5 alone. This effect was associated with a shift in the voltage dependence of K(+) channel activation to more positive potentials, consistent with findings of I(Kur) in atrial myocytes. FHL1 also increased the extent and speed of K(+) current slow inactivation, with additional effects on the voltage dependence and recovery of this process. These results support a role of FHL1 as a key molecular component in the I(Kur) complex in human atrium, where it likely regulates functional expression of KCNA5.
Publisher: Elsevier BV
Date: 09-1999
Start Date: 03-2019
End Date: 03-2022
Amount: $475,000.00
Funder: Australian Research Council
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