scholarly journals Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling

2017 ◽  
Vol 114 (4) ◽  
pp. 752-757 ◽  
Author(s):  
George Dalton ◽  
Sung-Wan An ◽  
Saif I. Al-Juboori ◽  
Nicole Nischan ◽  
Joonho Yoon ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lipid Rafts ◽  
Membrane Lipid ◽  
General Mechanism ◽  
Membrane Microdomains ◽  
Pi3k Signaling ◽  
Growth Factor Signaling ◽  
Paracrine Factor ◽  
Common Motif

Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane’s propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.

scholarly journals Spatiotemporal Analysis of Differential Akt Regulation in Plasma Membrane Microdomains

2008 ◽  
Vol 19 (10) ◽  
pp. 4366-4373 ◽  
Author(s):  
Xinxin Gao ◽  
Jin Zhang
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Lipid Rafts ◽  
Fluorescent Proteins ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Spatiotemporal Analysis ◽  
Membrane Microdomains ◽  
Cholesterol Depletion ◽  
Growth Factor Signaling

As a central kinase in the phosphatidylinositol 3-kinase pathway, Akt has been the subject of extensive research; yet, spatiotemporal regulation of Akt in different membrane microdomains remains largely unknown. To examine dynamic Akt activity in membrane microdomains in living cells, we developed a specific and sensitive fluorescence resonance energy transfer-based Akt activity reporter, AktAR, through systematic testing of different substrates and fluorescent proteins. Targeted AktAR reported higher Akt activity with faster activation kinetics within lipid rafts compared with nonraft regions of plasma membrane. Disruption of rafts attenuated platelet-derived growth factor (PDGF)-stimulated Akt activity in rafts without affecting that in nonraft regions. However, in insulin-like growth factor-1 (IGF)-1 stimulation, Akt signaling in nonraft regions is dependent on that in raft regions. As a result, cholesterol depletion diminishes Akt activity in both regions. Thus, Akt activities are differentially regulated in different membrane microdomains, and the overall activity of this oncogenic pathway is dependent on raft function. Given the increased abundance of lipid rafts in some cancer cells, the distinct Akt-activating characteristics of PDGF and IGF-1, in terms of both effectiveness and raft dependence, demonstrate the capabilities of different growth factor signaling pathways to transduce differential oncogenic signals across plasma membrane.

scholarly journals Role of IQGAP1 in Head and Neck Carcinogenesis

2018 ◽  
Author(s):  
Tao Wei ◽  
Suyong Choi ◽  
Darya Buehler ◽  
Alan C. Rapraeger ◽  
Richard A. Anderson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Human Cancer ◽  
Akt Signaling ◽  
Pi3k Signaling ◽  
Growth Factor Signaling ◽  
Iq Motif

ABSTRACTHead and neck squamous cell carcinoma (HNSCC) is a common cancer in humans. Phosphoinositide 3-kinase (PI3K)/AKT signaling, along with its downstream effector mTOR, is one of the most frequently altered pathways in HNSCC, and is downstream of growth factor signaling including that mediated by epidermal growth factor receptor (EGFR), which is also commonly upregulated in HNSCC. Recently, IQ motif-containing GTPase activation protein 1 (IQGAP1) has been reported to function as a scaffold for the enzymes involved in the PI3K/AKT signaling pathway. Iqgap1 gene expression is increased in human HNSCCs, raising the hypothesis that it acts as an oncogene in this cancer. Whether IQGAP1 is necessary for HNSCC development as well as what is its underlying mechanism are both unknown. Here we report on the role of IQGAP1 in HNSCC by performing a combination of in vitro studies using human cancer cell lines, and in vivo studies using a well-validated preclinical mouse model for HNSCC that is known to depend upon EGFR signaling. Cells knocked out for IQGAP1 lost AKT signaling. Disruption of IQGAP1-scaffolded PI3K/AKT signaling using a peptide that interferes with the ability of IQGAP1 to bind to PI3K reduced HNSCC cell survival. In vivo studies utilizing Iqgap1-null (Iqgap1-/-) mice demonstrated that IQGAP1 is necessary for efficient PI3K signaling upon EGF-stimulation. Treatment of Iqgap1-/- mice with the oral carcinogen, 4-nitroquinoline 1-oxide (4NQO), Iqgap1-/- led to significantly lower multiplicities of cancer foci as well as significantly lower numbers of high grade cancers than observed in similarly treated Iqgap1+/+ mice. IQGAP1 protein was increased in its expression in HNSCCs arising in the Iqgap1+/+ mice, consistent with that seen in human HNSCCs. We also observed a significant down-regulation of PI3K signaling in 4NQO-induced HNSCCs arising in the Iqgap1-/- mice, consistent with IQGAP1 contributing to carcinogenesis by promoting PI3K signaling. Our studies, therefore, support the hypothesis that IQGAP1 acts as an oncogene in head and neck carcinogenesis, and provide mechanistic insight into its role.

scholarly journals Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

2016 ◽  
Vol 113 (3) ◽  
pp. 769-774 ◽  
Author(s):  
Xiaoli Sun ◽  
Yi Fu ◽  
Mingxia Gu ◽  
Lu Zhang ◽  
Dan Li ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Shear Stress ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Density Lipoprotein ◽  
Membrane Lipid ◽  
Local Flow ◽  
Atherosclerotic Lesions ◽  
Integrin Α5

Local flow patterns determine the uneven distribution of atherosclerotic lesions. Membrane lipid rafts and integrins are crucial for shear stress-regulated endothelial function. In this study, we investigate the role of lipid rafts and integrin α5 in regulating the inflammatory response in endothelial cells (ECs) under atheroprone versus atheroprotective flow. Lipid raft proteins were isolated from ECs exposed to oscillatory shear stress (OS) or pulsatile shear stress, and then analyzed by quantitative proteomics. Among 396 proteins redistributed in lipid rafts, integrin α5 was the most significantly elevated in lipid rafts under OS. In addition, OS increased the level of activated integrin α5 in lipid rafts through the regulation of membrane cholesterol and fluidity. Disruption of F-actin-based cytoskeleton and knockdown of caveolin-1 prevented the OS-induced integrin α5 translocation and activation. In vivo, integrin α5 activation and EC dysfunction were observed in the atheroprone areas of low-density lipoprotein receptor-deficient (Ldlr−/−) mice, and knockdown of integrin α5 markedly attenuated EC dysfunction in partially ligated carotid arteries. Consistent with these findings, mice with haploinsufficency of integrin α5 exhibited a reduction of atherosclerotic lesions in the regions under atheroprone flow. The present study has revealed an integrin- and membrane lipid raft-dependent mechanotransduction mechanism by which atheroprone flow causes endothelial dysfunction.

scholarly journals Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling

2019 ◽  
Vol 30 (3) ◽  
pp. 525-538.e8 ◽  
Author(s):  
Junfeng Bi ◽  
Taka-Aki Ichu ◽  
Ciro Zanca ◽  
Huijun Yang ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Membrane Lipid ◽  
Growth Factor Signaling ◽  
Oncogene Amplification

scholarly journals Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2674-2680 ◽  
Author(s):  
Lisette M. Acevedo ◽  
Samuel Barillas ◽  
Sara M. Weis ◽  
Joachim R. Göthert ◽  
David A. Cheresh
Keyword(s):  
Growth Factor ◽  
Vascular Permeability ◽  
Growth Factor Signaling ◽  
Semaphorin 3A ◽  
Vascular Permeability Factor ◽  
Potent Inducer ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Neuropilin 1

Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, also alters vascular patterning. Here we show that Sema3A selectively interferes with VEGF- but not bFGF-induced angiogenesis in vivo. Consistent with this, Sema3A disrupted VEGF- but not bFGF-mediated endothelial cell signaling to FAK and Src, key mediators of integrin and growth factor signaling; however, signaling to ERK by either growth factor was unperturbed. Since VEGF is also a vascular permeability (VP) factor, we examined the role of Sema3A on VEGF-mediated VP in mice. Surprisingly, Sema3A not only stimulated VEGF-mediated VP but also potently induced VP in the absence of VEGF. Sema3A-mediated VP was inhibited either in adult mice expressing a conditional deletion of endothelial neuropilin-1 (Nrp-1) or in wild-type mice systemically treated with a function-blocking Nrp-1 antibody. While both Sema3A- and VEGF-induced VP was Nrp-1 dependent, they use distinct downstream effectors since VEGF- but not Sema3A-induced VP required Src kinase signaling. These findings define a novel role for Sema3A both as a selective inhibitor of VEGF-mediated angiogenesis and a potent inducer of VP.

scholarly journals Sulfatase modifying factor 1–mediated fibroblast growth factor signaling primes hematopoietic multilineage development

2010 ◽  
Vol 207 (8) ◽  
pp. 1647-1660 ◽  
Author(s):  
Mario Buono ◽  
Ilaria Visigalli ◽  
Roberta Bergamasco ◽  
Alessandra Biffi ◽  
Maria Pia Cosma
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
B Lymphocyte ◽  
Erythroid Differentiation ◽  
Growth Factor Signaling ◽  
Fibroblast Growth ◽  
Fgf Signaling ◽  
Cell Stage ◽  
Hematopoietic Stem

Self-renewal and differentiation of hematopoietic stem cells (HSCs) are balanced by the concerted activities of the fibroblast growth factor (FGF), Wnt, and Notch pathways, which are tuned by enzyme-mediated remodeling of heparan sulfate proteoglycans (HSPGs). Sulfatase modifying factor 1 (SUMF1) activates the Sulf1 and Sulf2 sulfatases that remodel the HSPGs, and is mutated in patients with multiple sulfatase deficiency. Here, we show that the FGF signaling pathway is constitutively activated in Sumf1−/− HSCs and hematopoietic stem progenitor cells (HSPCs). These cells show increased p-extracellular signal-regulated kinase levels, which in turn promote β-catenin accumulation. Constitutive activation of FGF signaling results in a block in erythroid differentiation at the chromatophilic erythroblast stage, and of B lymphocyte differentiation at the pro–B cell stage. A reduction in mature myeloid cells and an aberrant development of T lymphocytes are also seen. These defects are rescued in vivo by blocking the FGF pathway in Sumf1−/− mice. Transplantation of Sumf1−/− HSPCs into wild-type mice reconstituted the phenotype of the donors, suggesting a cell autonomous defect. These data indicate that Sumf1 controls HSPC differentiation and hematopoietic lineage development through FGF and Wnt signaling.

scholarly journals AIB1 Is a Conduit for Kinase-Mediated Growth Factor Signaling to the Estrogen Receptor

2000 ◽  
Vol 20 (14) ◽  
pp. 5041-5047 ◽  
Author(s):  
Jaime Font de Mora ◽  
Myles Brown
Keyword(s):  
Estrogen Receptor ◽  
Growth Factors ◽  
Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Growth Factor Signaling ◽  
Breast Cancers ◽  
Mapk Activation ◽  
Mitogen Activated Protein

ABSTRACT Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

scholarly journals Dynamics of putative raft-associated proteins at the cell surface

2004 ◽  
Vol 165 (5) ◽  
pp. 735-746 ◽  
Author(s):  
Anne K. Kenworthy ◽  
Benjamin J. Nichols ◽  
Catha L. Remmert ◽  
Glenn M. Hendrix ◽  
Mukesh Kumar ◽  
...  
Keyword(s):  
Cell Surface ◽  
Lipid Rafts ◽  
Long Range ◽  
Dominant Factor ◽  
Membrane Microdomains ◽  
Cholesterol Depletion ◽  
Biochemical Fractionation ◽  
Associated Proteins ◽  
Raft Domains

Lipid rafts are conceptualized as membrane microdomains enriched in cholesterol and glycosphingolipid that serve as platforms for protein segregation and signaling. The properties of these domains in vivo are unclear. Here, we use fluorescence recovery after photobleaching to test if raft association affects a protein's ability to laterally diffuse large distances across the cell surface. The diffusion coefficients (D) of several types of putative raft and nonraft proteins were systematically measured under steady-state conditions and in response to raft perturbations. Raft proteins diffused freely over large distances (>4 μm), exhibiting Ds that varied 10-fold. This finding indicates that raft proteins do not undergo long-range diffusion as part of discrete, stable raft domains. Perturbations reported to affect lipid rafts in model membrane systems or by biochemical fractionation (cholesterol depletion, decreased temperature, and cholesterol loading) had similar effects on the diffusional mobility of raft and nonraft proteins. Thus, raft association is not the dominant factor in determining long-range protein mobility at the cell surface.

scholarly journals Tumors overcome the action of the wasting factor ImpL2 by locally elevating Wnt/Wingless

2021 ◽  
Vol 118 (23) ◽  
pp. e2020120118
Author(s):  
Jiae Lee ◽  
Katelyn G.-L. Ng ◽  
Kenneth M. Dombek ◽  
Dae Seok Eom ◽  
Young V. Kwon
Keyword(s):  
Growth Factor ◽  
General Mechanism ◽  
Growth Factor Signaling ◽  
Insulin Like Growth Factor ◽  
Muscle Degeneration ◽  
Related Protein ◽  
Efficient Treatment ◽  
Factors Associated ◽  
Induced Tumors ◽  
Host Tissues

Tumors often secrete wasting factors associated with atrophy and the degeneration of host tissues. If tumors were to be affected by the wasting factors, mechanisms allowing tumors to evade the adverse effects of the wasting factors must exist, and impairing such mechanisms may attenuate tumors. We use Drosophila midgut tumor models to show that tumors up-regulate Wingless (Wg) to oppose the growth-impeding effects caused by the wasting factor, ImpL2 (insulin-like growth factor binding protein [IGFBP]-related protein). Growth of Yorkie (Yki)-induced tumors is dependent on Wg while either elimination of ImpL2 or elevation of insulin/insulin-like growth factor signaling in tumors revokes this dependency. Notably, Wg augmentation could be a general mechanism for supporting the growth of tumors with elevated ImpL2 and exploited to attenuate muscle degeneration during wasting. Our study elucidates the mechanism by which tumors negate the action of ImpL2 to uphold their growth during cachexia-like wasting and implies that targeting the Wnt/Wg pathway might be an efficient treatment strategy for cancers with elevated IGFBPs.

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