Insulin‐stimulated glucose uptake partly relies on p21‐activated kinase (PAK)2, but not PAK1, in mouse skeletal muscle

Møller, Lisbeth L. V.; Jaurji, Merna; Kjøbsted, Rasmus; Joseph, Giselle A.; Madsen, Agnete B.; Knudsen, Jonas R.; Lundsgaard, Anne‐Marie; Andersen, Nicoline R.; Schjerling, Peter; Jensen, Thomas E.; Krauss, Robert M.; Richter, Erik A.; Sylow, Lykke

doi:10.1113/jp280294

Cited by 16 publications

(23 citation statements)

References 72 publications

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“…PAK1 KO mouse muscles also displayed diminished insulin-stimulated GLUT4 translocation (Wang et al, 2011). On the other hand, another study reported normal insulin-stimulated glucose uptake in vivo and in isolated muscle of PAK1 KO mice, whereas insulin-stimulated glucose uptake was slightly reduced in muscle-specific PAK2 KO mice (Møller et al, 2020).…”

Section: Insulin Signaling To Glut4 In Musclementioning

confidence: 94%

“…Whether PAK1 is required for insulin-stimulated glucose uptake in skeletal muscle is so far controversial. On one hand, pharmacological inhibition of PAK isoforms abolished insulinstimulated GLUT4 translocation and glucose uptake in myoblasts and myotubes (Tunduguru et al, 2014) and partially reduced the glucose response in mouse skeletal muscle (Møller et al, 2020). PAK1 KO mouse muscles also displayed diminished insulin-stimulated GLUT4 translocation (Wang et al, 2011).…”

Section: Insulin Signaling To Glut4 In Musclementioning

confidence: 99%

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The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

et al. 2021

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Section: Insulin Signaling To Glut4 In Musclementioning

confidence: 94%

Section: Insulin Signaling To Glut4 In Musclementioning

confidence: 99%

The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

et al. 2021

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“…In addition, several studies have linked both PAK1 and PAK2 to the regulation of glucose homeostasis [ 51 , 52 , 53 ]. However, a recent study by the Sylow lab challenges this, suggesting that insulin-stimulated glucose uptake relies partly on PAK2, but not PAK1 [ 54 ]. Glucose tolerance in vivo and the insulin-stimulated uptake of 2-deoxy-D-glucose into extensor digitorum longus muscle ex vivo were mildly impaired in mice lacking PAK2, but not PAK1, using muscle-specific deletion [ 54 ].…”

Section: Rho Family Gtpases and Rho Gefsmentioning

confidence: 99%

“…However, a recent study by the Sylow lab challenges this, suggesting that insulin-stimulated glucose uptake relies partly on PAK2, but not PAK1 [ 54 ]. Glucose tolerance in vivo and the insulin-stimulated uptake of 2-deoxy-D-glucose into extensor digitorum longus muscle ex vivo were mildly impaired in mice lacking PAK2, but not PAK1, using muscle-specific deletion [ 54 ]. In addition to WAVE and PAKs, Rac1 also activates the cofilin phosphatase slingshot1 (Ssh1), leading to cofilin inactivation [ 55 ].…”

Section: Rho Family Gtpases and Rho Gefsmentioning

confidence: 99%

Rho Family GTPases and Rho GEFs in Glucose Homeostasis

Machin

Tsonou

Hornigold

et al. 2021

Cells

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Dysregulation of glucose homeostasis leading to metabolic syndrome and type 2 diabetes is the cause of an increasing world health crisis. New intriguing roles have emerged for Rho family GTPases and their Rho guanine nucleotide exchange factor (GEF) activators in the regulation of glucose homeostasis. This review summates the current knowledge, focusing in particular on the roles of Rho GEFs in the processes of glucose-stimulated insulin secretion by pancreatic β cells and insulin-stimulated glucose uptake into skeletal muscle and adipose tissues. We discuss the ten Rho GEFs that are known so far to regulate glucose homeostasis, nine of which are in mammals, and one is in yeast. Among the mammalian Rho GEFs, P-Rex1, Vav2, Vav3, Tiam1, Kalirin and Plekhg4 were shown to mediate the insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane and/or insulin-stimulated glucose uptake in skeletal muscle or adipose tissue. The Rho GEFs P-Rex1, Vav2, Tiam1 and β-PIX were found to control the glucose-stimulated release of insulin by pancreatic β cells. In vivo studies demonstrated the involvement of the Rho GEFs P-Rex2, Vav2, Vav3 and PDZ-RhoGEF in glucose tolerance and/or insulin sensitivity, with deletion of these GEFs either contributing to the development of metabolic syndrome or protecting from it. This research is in its infancy. Considering that over 80 Rho GEFs exist, it is likely that future research will identify more roles for Rho GEFs in glucose homeostasis.

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“…There are six members in PAKs family, which are divided into two groups based on the sequence and structure homology: group I PAKs (including PAK1, PAK2, and PAK3) and group II PAKs (including PAK4, PAK5, and PAK6). Among all PAKs, PAK1, and PAK4 have been well studied, and other PAKs are getting researchers’ interest ( Geng et al, 2020 ; Maruta and Kittaka, 2020 ; Møller et al, 2020 ; Ruan et al, 2020 ; Zheng et al, 2020 ). Most of the PAKs have oncogenic effects on cancer development.…”

Section: Introductionmentioning

confidence: 99%

The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?

Liu

Dong

2021

Front. Cell Dev. Biol.

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The p21-activated kinases (PAKs), downstream effectors of Ras-related Rho GTPase Cdc42 and Rac, are serine/threonine kinases. Biologically, PAKs participate in various cellular processes, including growth, apoptosis, mitosis, immune response, motility, inflammation, and gene expression, making PAKs the nexus of several pathogenic and oncogenic signaling pathways. PAKs were proved to play critical roles in human diseases, including cancer, infectious diseases, neurological disorders, diabetes, pancreatic acinar diseases, and cardiac disorders. In this review, we systematically discuss the structure, function, alteration, and molecular mechanisms of PAKs that are involved in the pathogenic and oncogenic effects, as well as PAK inhibitors, which may be developed and deployed in cancer therapy, anti-viral infection, and other diseases. Furthermore, we highlight the critical questions of PAKs in future research, which provide an opportunity to offer input and guidance on new directions for PAKs in pathogenic, oncogenic, and drug discovery research.

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Insulin‐stimulated glucose uptake partly relies on p21‐activated kinase (PAK)2, but not PAK1, in mouse skeletal muscle

Cited by 16 publications

References 72 publications

The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia

Rho Family GTPases and Rho GEFs in Glucose Homeostasis

The Role of p21-Activated Kinases in Cancer and Beyond: Where Are We Heading?

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