Non-prenylatable, cytosolic Rac1 alters neurite outgrowth while retaining the ability to be activated

Reddy, Jairus M.; Samuel, Filsy; McConnell, Jordan A.; Reddy, Cristina P.; Beck, Brian W.; Hynds, DiAnna L.

doi:10.1016/j.cellsig.2014.11.033

Cited by 12 publications

(11 citation statements)

References 33 publications

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“…Along these lines, Dunford et al have showed constitutive activation of Rac, Cdc42 and Rho G‐proteins in J774 macrophages following inhibition of prenylation by nitrogen‐containing bisphosphonates. Along these lines published evidence suggests significant alterations in subcellular distribution (mistargeting) of G‐proteins under conditions in which their prenylation is suppressed via mutation of prenylatable cysteine in the CAAX motif . Taken together, these findings show inhibition of prenylation results in sustained activation and translocation of G‐proteins to inappropriate cellular compartments, thus raising an important question if such a signalling step leads to cellular pathology including islet dysfunction.…”

Section: G‐protein Prenylation In Islet β‐Cell Function and Dysfunctionmentioning

confidence: 84%

Role of G‐proteins in islet function in health and diabetes

Kowluru

2017

Diabetes Obesity Metabolism

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Glucose-stimulated insulin secretion [GSIS] involves interplay between metabolic and cationic events. Seminal contributions from multiple laboratories affirm essential roles for small G-proteins [Rac1, Cdc42, Arf6, Rab27A] in GSIS. Activation of these signaling proteins promotes cytoskeletal remodeling, transport and docking of insulin granules on the plasma membrane for exocytotic secretion of insulin. Evidence in rodent and human islets suggests key roles for lipidation [farnesylation and geranylgeranylation] of these G-proteins for their targeting to appropriate cellular compartments for optimal regulation of effectors leading to GSIS. Interestingly, however, inhibition of prenylation appears to cause mislocalization of non-prenylated, but [paradoxically] activated G-proteins, in “inappropriate” compartments leading to activation of stress kinases and onset of mitochondrial defects, loss in GSIS and apoptosis of the islet β-cell. This review highlights our current understanding of roles of G-proteins and their posttranslational lipidation [prenylation] signaling networks in islet function in normal health, metabolic stress [glucolipotoxicity and ER stress] and diabetes. Critical knowledge gaps that need to be addressed for the development of therapeutics to halt defects in these signaling steps in β cells in models of impaired insulin secretion and diabetes are also highlighted and discussed.

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Section: G‐protein Prenylation In Islet β‐Cell Function and Dysfunctionmentioning

confidence: 84%

Role of G‐proteins in islet function in health and diabetes

Kowluru

2017

Diabetes Obesity Metabolism

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“…Indeed, the critical role of prenylated Rac1 in dendritic morphogenesis has been shown previously; deletion or mutation of the geranylgeranylation site in Rac1 fails to mediate the beneficial effects of GGT overexpression on dendritic arborization in cultured neurons (Zhou et al, 2008). Using a similar approach, another study reported that expression of a non-prenylated Rac1 led to abnormal cell morphology and neurite initiation because of aberrant activation of cytosolic signaling pathways (Reddy et al, 2015). Therefore, reduction of dendritic spine density and synaptic plasticity in GGT-deficient mice most likely result from inadequate geranylgeranylation and dysfunction of these Rho proteins.…”

Section: Discussionmentioning

confidence: 99%

Systemic or Forebrain Neuron-Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density

et al. 2018

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Isoprenoids and prenylated proteins regulate a variety of cellular functions, including neurite growth and synaptic plasticity. Importantly, they are implicated in the pathogenesis of several diseases, including Alzheimer's disease (AD). Recently, we have shown that two protein prenyltransferases, farnesyltransferase (FT) and geranylgeranyltransferase-1 (GGT), have differential effects in a mouse model of AD. Haplodeficiency of either FT or GGT attenuates amyloid-β deposition and neuroinflammation but only reduction in FT rescues cognitive function. The current study aimed to elucidate the potential mechanisms that may account for the lack of cognitive benefit in GGT-haplodeficient mice, despite attenuated neuropathology. The results showed that the magnitude of long-term potentiation (LTP) was markedly suppressed in hippocampal slices from GGT-haplodeficient mice. Consistent with the synaptic dysfunction, there was a significant decrease in cortical spine density and cognitive function in GGT-haplodeficient mice. To further study the neuron-specific effects of GGT deficiency, we generated conditional forebrain neuron-specific GGT-knockout (GGTCre+) mice using a Cre/LoxP system under the CAMKIIα promoter. We found that both the magnitude of hippocampal LTP and the dendritic spine density of cortical neurons were decreased in GGTCre+ mice compared with GGTCre- mice. Immunoblot analyses of cerebral lysate showed a significant reduction in cell membrane-associated (geranylgeranylated) Rac1 and RhoA but not (farnesylated) H-Ras, in GGTCre+ mice, suggesting that insufficient geranylgeranylation of the Rho family of small GTPases may underlie the detrimental effects of GGT deficiency. These findings reinforce the critical role of GGT in maintaining spine structure and synaptic/cognitive function in development and in the mature brain.

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“…Non prenylatable [GFP Rac1-C189A] Rac1 construct was prepared as described in [29]. Myc-Rac1 wild type and dominant negative N17 Myc-Rac1 constructs were from cDNA Resource Center [Bloomsberg, PA].…”

Section: Methodsmentioning

confidence: 99%

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

et al. 2017

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Emerging evidence suggests that long-term exposure of insulin-secreting pancreatic β-cells to hyperglycemic [HG; glucotoxic] conditions promotes oxidative stress, which, in turn, leads to stress kinase activation, mitochondrial dysfunction, loss of nuclear structure and integrity and cell apoptosis. Original observations from our laboratory have proposed that Rac1 plays a key regulatory role in the generation of oxidative stress and downstream signaling events culminating in the onset of dysfunction of pancreatic β-cells under the duress of metabolic stress. However, precise molecular and cellular mechanisms underlying the metabolic roles of hyperactive Rac1 remain less understood. Using pharmacological and molecular biological approaches, we now report mistargetting of biologically-active Rac1 [GTP-bound conformation] to the nuclear compartment in clonal INS-1 cells, normal rat islets and human islets under HG conditions. Our findings also suggest that such a signaling step is independent of post-translational prenylation of Rac1. Evidence is also presented to highlight novel roles for sustained activation of Rac1 in HG-induced expression of Cluster of Differentiation 36 [CD36], a fatty acid transporter protein, which is implicated in cell apoptosis. Finally, our findings suggest that metformin, a biguanide anti-diabetic drug, at a clinically relevant concentration, prevents β-cell defects [Rac1 activation, nuclear association, CD36 expression, stress kinase and caspase-3 activation, and loss in metabolic viability] under the duress of glucotoxicity. Potential implications of these findings in the context of novel and direct regulation of islet β-cell function by metformin are discussed.

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Non-prenylatable, cytosolic Rac1 alters neurite outgrowth while retaining the ability to be activated

Cited by 12 publications

References 33 publications

Role of G‐proteins in islet function in health and diabetes

Role of G‐proteins in islet function in health and diabetes

Systemic or Forebrain Neuron-Specific Deficiency of Geranylgeranyltransferase-1 Impairs Synaptic Plasticity and Reduces Dendritic Spine Density

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin

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