Cytoskeleton Dynamics in Health and Disease: Role of Molecular Switches and Rheostats

Osman, Mahasin A.

doi:10.1007/978-1-4939-2904-7_2

Cited by 4 publications

(10 citation statements)

References 348 publications

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“…As shown in Figure 1A, IQGAP1 is a modular protein involved in many cellular functions [17,19]. Previously, we demonstrated that IQGAP1 acts as a phosphorylation-dependent conformation switch that regulates insulin secretion, cell size and proliferation [24,27,44].…”

Section: Iqgap1 Localizes To the Centrosome And Impacts Centrosome Simentioning

confidence: 93%

“…downstream targets in a context-dependent manner [19,22,23]. IQGAP1 modulates oncogenic pathways like mTOR-S6K-Akt pathway and the mitogen protein kinase (MAPK) Erk1/2 [23,24], and controls adheren and tight junctions in epithelial cells by regulating the E-cadherinβ-catenin complex [25,26].…”

Section: Research Papermentioning

confidence: 99%

“…Aberrant activity of the IQ-containing GTPase Activating Protein (IQGAP1) associates with many carcinomas, including TNBC [17][18][19]. While overexpression of IQGAP1 has been implicated in these carcinomas and proposed as clinical target [19][20][21], its mechanism is just emerging. IQGAP1 is a regulatory scaffold with remarkable signaling versatility stemming from its ability to assemble signaling sub-complexes that respond to various stimuli and generate highly specific cellular responses by selecting the appropriate…”

Section: Introductionmentioning

confidence: 99%

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IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer

Osman

James

Yakirevich³

2020

Oncotarget

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Triple negative breast cancer (TNBC) is a heterogenous and lethal disease that lacks diagnostic markers and therapeutic targets; as such common targets are highly sought after. IQGAP1 is a signaling scaffold implicated in TNBC, but its mechanism is unknown. Here we show that IQGAP1 localizes to the centrosome, interacts with and influences the expression level and localization of key centrosome proteins like BRCA1 and thereby impacts centrosome number. Genetic mutant analyses suggest that phosphorylation cycling of IQGAP1 is important to its subcellular localization and centrosome-nuclear shuttling of BRCA1; dysfunction of this process defines two alternate mechanisms associated with cell proliferation. TNBC cell lines and patient tumor tissues differentially phenocopy these mechanisms supporting clinical existence of molecularly distinct variants of TNBC defined by IQGAP1 pathways. These variants are defined, at least in part, by differential mis-localization or stabilization of IQGAP1-BRCA1 and rewiring of a novel Erk1/2-MNK1-JNK-Akt-β-catenin signaling signature. We discuss a model in which IQGAP1 modulates centrosome-nuclear crosstalk to regulate cell division and imparts on cancer. These findings have implications on cancer racial disparities and can provide molecular tools for classification of TNBC, presenting IQGAP1 as a common target amenable to personalized medicine.

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Section: Iqgap1 Localizes To the Centrosome And Impacts Centrosome Simentioning

confidence: 93%

Section: Research Papermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer

Osman

James

Yakirevich³

2020

Oncotarget

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“…The MAPK component ERK1/2 triggers a signaling cascade of the MAPK superfamily proteins that regulate cell cycle and cell proliferation [16,20]. Research has also shown that EGFR colocalizes with the IQ motif-containing GTPase Activating Protein 1 (IQGAP1), a scaffold oncoprotein that regulates a plethora of cellular functions, including cell-cell contacts, cell motility, cell division and proliferation, protein tra c, and apoptosis [21,22]; however, its underlying mechanisms in these various events are just emerging as discussed later below. PTEN is a tumor suppressor that has been identi ed as a frequent GB target because its mutations promote uncontrolled and rapid tumor progression [23].…”

Section: Identi Ed Molecular Targets In Gbmentioning

confidence: 99%

Role of Scaffold Proteins in the Heterogeneity of Glioblastoma

Iyer,

Donahue,

Osman

2024

Preprint

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Glioblastoma (GB) is a highly heterogeneous type of incurable brain cancer with a low survival rate. Intensive ongoing research has identified several potential targets; however, GB is marred by the activation of multiple pathways, and thus common targets are highly sought after. The signal regulatory scaffold IQGAP1 is an oncoprotein implicated in GB. IQGAP1 nucleates a myriad of pathways in a contextual manner and modulates many of the targets altered in GB like MAPK, NF-κB, and mTOR/PI3K/Akt1, thus positioning it as a plausible common therapeutic target. Here, we review the targets that are subjects of GB treatment clinical trials and the commonly used animal models that facilitate target identification. We propose a model in which the dysfunction of various IQGAP1 pathways can explain to a larger extent some of the GB heterogeneity and offer a platform for personalized medicine.

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“…Biochemical and patch-clamp studies showed that IQGAP1 [ 96 ] and SigmaR1 [ 97 ] interact with the ionotropic glutamate N-methyl-D-aspartate receptor (NMDR) in the neurons and influence synaptic processes. Additionally, IQGAP1 localizes to the same subcellular regions as SigmaR1, including the plasma membrane, the nuclear envelope and the ER, and is involved in similar disease outcomes such as cancer and diabetes [ 98 ]. Taken together, these findings may help explain why SigmaR1 promotes oncogenic growth while itself is not an oncoprotein and provide avenues for utilizing SigmaR1 in personalized medicine.…”

Section: Perspective: Sigmar1 As An Adaptor Protein In Key Cellular F...mentioning

confidence: 99%

An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer

Robinson

Osman

2023

Cancers

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Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub-cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine.

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Cytoskeleton Dynamics in Health and Disease: Role of Molecular Switches and Rheostats

Cited by 4 publications

References 348 publications

IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer

IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer

Role of Scaffold Proteins in the Heterogeneity of Glioblastoma

An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer

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