GTPase splice variants RAC1 and RAC1B display isoform-specific differences in localization, prenylation, and interaction with the chaperone protein SmgGDS

Koehn, Olivia J.; Lorimer, Ellen L.; Unger, Bethany; Harris, Ra’Mal; Das, Akansha S.; Suazo, Kiall F.; Auger, Shelby A.; Distefano, Mark D.; Prokop, Jeremy W.; Williams, Carol L.

doi:10.1016/j.jbc.2023.104698

Cited by 7 publications

(5 citation statements)

References 58 publications

(156 reference statements)

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“…If RAC1b is to activate TAp73 then it should be located in the nucleus. In fact, nuclear localization of RAC1b has been reported and compared to the parental isoform, RAC1, RAC1b more strongly accumulates in the nucleus as a result of less prenylation, which in turn is due to a more stable association with SmgGDS-607 [24]. This spatial proximity to TAp73 may explain why RAC1b can induce SMAD4 via TAp73 binding to the DPC4 promoter.…”

Section: Discussionmentioning

confidence: 97%

RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

Ungefroren,

Reimann,

Konukiewitz

et al. 2023

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease due to early metastatic spread, late diagnosis and the lack of efficient therapies. A major driver of cancer progression and hurdle to successful treatment is the desmoplastic reaction of the tumor stroma, the formation of which is orchestrated by transforming growth factor (TGF)-β. Recent data from pancreatic cancer mouse models have shown that the TGF-β pathway is controlled by transcriptionally active p73 (TAp73) through secretion of biglycan (Bgn) via intermittent expression of the TGF-β signaling intermediates, Smad3 and Smad4. Genetic knockout of TP73, and, as a consequence, deficient induction of Smad3/Dpc4 and secretion of Bgn led to activation of TGF-β signaling through a (Smad-independent) ERK pathway, favoring epithelial-mesenchymal transition (EMT) and cell motility. Except for BGN, these functions of TAp73 have recently been shown to also operate in human PDAC cells and are reminiscent of what we previously observed for the small GTPase, RAC1b. This prompted us to hypothesize that TAp73 and RAC1b are part of the same tumor-suppressive pathway in human PDAC cells. The two objectives of this study, therefore, were to reveal i) if the regulatory interactions between TAp73 and Bgn previously discovered in murine PDAC-derived cells also operate in their human counterparts, and ii) if RAC1b collaborates with TAp73 in these tumor-suppressive activities in human PDAC cells. Using a variety of experimental approaches, including mutual rescue experiments, we were able to show that the previously proposed tumor-suppressive TAp73-Smad4-Bgn signaling also operates in human cells and that RAC1b is as an upstream activator of this pathway. Our findings highlight the complex role of TGF-β in pancreatic tumorigenesis and might have implications for therapeutic approaches targeting this growth factor for inhibition.

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Section: Discussionmentioning

confidence: 97%

RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

Ungefroren,

Reimann,

Konukiewitz

et al. 2023

Preprint

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show abstract

“…In fact, nuclear localization of RAC1b has been reported and compared to the parental isoform, RAC1. Interestingly, RAC1b more strongly accumulates in the nucleus as a result of less prenylation, which in turn is due to a more stable association with SmgGDS-607 [26]. This spatial proximity to TAp73 may explain why RAC1b can induce SMAD4 via TAp73 binding to the DPC4 promoter.…”

Section: Discussionmentioning

confidence: 99%

RAC1b Collaborates with TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

Ungefroren,

Reimann,

Konukiewitz

et al. 2024

Biomedicines

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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type characterized by a marked desmoplastic tumor stroma that is formed under the influence of transforming growth factor (TGF)-β. Data from mouse models of pancreatic cancer have revealed that transcriptionally active p73 (TAp73) impacts the TGF-β pathway through activation of Smad4 and secretion of biglycan (Bgn). However, whether this pathway also functions in human PDAC cells has not yet been studied. Here, we show that RNA interference-mediated silencing of TAp73 in PANC-1 cells strongly reduced the stimulatory effect of TGF-β1 on BGN. TAp73-mediated regulation of BGN, and inhibition of TGF-β signaling through a (Smad-independent) ERK pathway, are reminiscent of what we previously observed for the small GTPase, RAC1b, prompting us to hypothesize that in human PDAC cells TAp73 and RAC1b are part of the same tumor-suppressive pathway. Like TAp73, RAC1b induced SMAD4 protein and mRNA expression. Moreover, siRNA-mediated knockdown of RAC1b reduced TAp73 mRNA levels, while ectopic expression of RAC1b increased them. Inhibition of BGN synthesis or depletion of secreted BGN from the culture medium reproduced the promigratory effect of RAC1b or TAp73 silencing and was associated with increased basal and TGF-β1-dependent ERK activation. BGN also phenocopied the effects of RAC1b or TAp73 on the expression of downstream effectors, like the EMT markers E-cadherin, Vimentin and SNAIL, as well as on negative regulation of the ALK2-SMAD1/5 arm of TGF-β signaling. Collectively, we showed that tumor-suppressive TAp73-Smad4-Bgn signaling also operates in human cells and that RAC1b likely acts as an upstream activator of this pathway.

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“…Efferocytosis-related molecules such as G protein-coupled receptor G2A ( 108 ), CD300 family member CD300f ( 109 ), integrins ( 110 ), and RAC1 ( 111 ) have been shown to be linked to inflammatory bowel disease/colitis. CD36 is also linked to diet-induced obesity ( 112 , 113 ).…”

Section: Pathological Contexts Involving Efferocytosis By Macrophagesmentioning

confidence: 99%

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms

Sheng,

Hu,

Chen

et al. 2024

Front. Immunol.

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Efferocytosis is defined as the highly effective phagocytic removal of apoptotic cells (ACs) by professional or non-professional phagocytes. Tissue-resident professional phagocytes (“efferocytes”), such as macrophages, have high phagocytic capacity and are crucial to resolve inflammation and aid in homeostasis. Recently, numerous exciting discoveries have revealed divergent (and even diametrically opposite) findings regarding metabolic immune reprogramming associated with efferocytosis by macrophages. In this review, we highlight the key metabolites involved in the three phases of efferocytosis and immune reprogramming of macrophages under physiological and pathological conditions. The next decade is expected to yield further breakthroughs in the regulatory pathways and molecular mechanisms connecting immunological outcomes to metabolic cues as well as avenues for “personalized” therapeutic intervention.

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GTPase splice variants RAC1 and RAC1B display isoform-specific differences in localization, prenylation, and interaction with the chaperone protein SmgGDS

Cited by 7 publications

References 58 publications

RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

RAC1b Acts Upstream of TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

RAC1b Collaborates with TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms

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