Regulation and functions of the RhoA regulatory guanine nucleotide exchange factor GEF-H1

Joo, Emily; Olson, Michael F.

doi:10.1080/21541248.2020.1840889

Cited by 31 publications

(23 citation statements)

References 142 publications

(236 reference statements)

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“…Taken together, compartmentally regulated increases in actin polymerization shift MRTF to the nucleus, and unleash its transcriptional potential. A plethora of factors (e.g., guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) [ 9 , 70 , 71 , 72 ] regulate Rho GTPases and/or induce posttranslational modification of proteins involved in actin sequestering (e.g., thymosin [ 73 ]), severing (e.g., cofilin [ 36 , 74 , 75 , 76 ]) and polymerization (e.g., mDIA [ 69 , 77 ]) or modify actin itself [ 78 ]. All of these regulate MRTF, which thus emerged as a major highway connecting cytoskeletal state to gene expression.…”

Section: Mrtfs: Their Discovery and Modus Operandimentioning

confidence: 99%

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

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A lesser known but crucially important downstream effect of Rho family GTPases is the regulation of gene expression. This major role is mediated via the cytoskeleton, the organization of which dictates the nucleocytoplasmic shuttling of a set of transcription factors. Central among these is myocardin-related transcription factor (MRTF), which upon actin polymerization translocates to the nucleus and binds to its cognate partner, serum response factor (SRF). The MRTF/SRF complex then drives a large cohort of genes involved in cytoskeleton remodeling, contractility, extracellular matrix organization and many other processes. Accordingly, MRTF, activated by a variety of mechanical and chemical stimuli, affects a plethora of functions with physiological and pathological relevance. These include cell motility, development, metabolism and thus metastasis formation, inflammatory responses and—predominantly-organ fibrosis. The aim of this review is twofold: to provide an up-to-date summary about the basic biology and regulation of this versatile transcriptional coactivator; and to highlight its principal involvement in the pathobiology of kidney disease. Acting through both direct transcriptional and epigenetic mechanisms, MRTF plays a key (yet not fully appreciated) role in the induction of a profibrotic epithelial phenotype (PEP) as well as in fibroblast-myofibroblast transition, prime pathomechanisms in chronic kidney disease and renal fibrosis.

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Section: Mrtfs: Their Discovery and Modus Operandimentioning

confidence: 99%

MRTF: Basic Biology and Role in Kidney Disease

Miranda

Lichner

Szászi

et al. 2021

IJMS

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“…This approach allowed us to directly demonstrate that EB1 in developing human cortical neurons is required for sustained growth cone MT growth and growth cone advance. Although we do not completely dissect the molecular mechanism underlying the π-EB1 photodissociation-mediated neurite retraction response, unchanged f-actin polymerization dynamics during blue light indicate that retraction likely results from a loss of growth cone adhesion or an increase in neurite actomyosin contractility consistent with MT-shortening induced RhoA activation (Joo and Olson, 2021). An increase in neurite contractility that does not remain localized to the region of blue light exposure may also explain our difficulty in using π-EB1 photodissociation to control growth cone guidance more precisely.…”

Section: Resultsmentioning

confidence: 94%

Growth cone advance requires EB1 as revealed by genomic replacement with a light-sensitive variant

Dema

Charafeddine

Rahgozar

et al. 2022

Preprint

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A challenge in analyzing dynamic intracellular cell biological processes is the dearth of methodologies that are sufficiently fast and specific to perturb intracellular protein activities. We previously developed a light-sensitive variant of the microtubule plus end tracking protein EB1 by inserting a blue light-controlled protein dimerization module between functional domains. Here we describe an advanced method to replace endogenous EB1 with this light-sensitive variant in a single genome editing step enabling this approach in human induced pluripotent stem cells and derived neurons. We demonstrate that acute and local optogenetic EB1 inactivation in developing cortical neurons induces microtubule depolymerization in the growth cone periphery and subsequent neurite retraction. In addition, advancing growth cones are repelled from areas of blue light exposure. These phenotypes were independent of the neuronal EB1 homolog EB3, revealing a direct dynamic role of EB1-mediated microtubule plus end interactions in neuron morphogenesis and neurite guidance.

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“…ARHGEF2 can bind directly to microtubules and is involved in the regulation of numerous processes. These include dendritic spine morphology, focal adhesions, cell motility, regulation of polarization during the cell cycle regulation and epithelial barrier permeability ( Figure 2C ) [ 104 ]. Disruption of these processes has been well-recorded in CDKL5-deficient cells (as discussed above), and disrupted phosphorylation of ARHGEF2 may explain some of these processes.…”

Section: Cdkl5 Phosphorylation Targets Containing the Consensus Motifmentioning

confidence: 99%

CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development

Bergen

Massey

Quigley

et al. 2022

Biochemical Society Transactions

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CDKL5 deficiency disorder (CDD) is an X-linked brain disorder of young children and is caused by pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene. Individuals with CDD suffer infantile onset, drug-resistant seizures, severe neurodevelopmental impairment and profound lifelong disability. The CDKL5 protein is a kinase that regulates key phosphorylation events vital to the development of the complex neuronal network of the brain. Pathogenic variants identified in patients may either result in loss of CDKL5 catalytic activity or are hypomorphic leading to partial loss of function. Whilst the progressive nature of CDD provides an excellent opportunity for disease intervention, we cannot develop effective therapeutics without in-depth knowledge of CDKL5 function in human neurons. In this mini review, we summarize new findings on the function of CDKL5. These include CDKL5 phosphorylation targets and the consequence of disruptions on signaling pathways in the human brain. This new knowledge of CDKL5 biology may be leveraged to advance targeted drug discovery and rapid development of treatments for CDD. Continued development of effective humanized models will further propel our understanding of CDD biology and may permit the development and testing of therapies that will significantly alter CDD disease trajectory in young children.

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Regulation and functions of the RhoA regulatory guanine nucleotide exchange factor GEF-H1

Cited by 31 publications

References 142 publications

MRTF: Basic Biology and Role in Kidney Disease

MRTF: Basic Biology and Role in Kidney Disease

Growth cone advance requires EB1 as revealed by genomic replacement with a light-sensitive variant

CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development

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