YES, a Src Family Kinase, Is a Proximal Glucose-specific Activator of Cell Division Cycle Control Protein 42 (Cdc42) in Pancreatic Islet β Cells

Yoder, Stephanie M.; Dineen, Stacey L.; Wang, Zhanxiang; Thurmond, Debbie C.

doi:10.1074/jbc.m114.559328

Cited by 37 publications

(35 citation statements)

References 73 publications

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“…However, in smooth muscle cells SFK activation was not needed for the angiotensin II-mediated activation of PAK[85]. These findings that activation of SFKs is frequently upstream of PAKs activation are consistent with studies demonstrating SFKs are important in the activation of the PAK activators, Rac and CDC42, by a number of stimulants[103,106,107]. These results reveal that the GI hormone/neurotransmitter, CCK, demonstrates a number of unique features related to its receptor activation-state in activating signaling cascades to stimulate PAK2 activation.…”

Section: Discussionsupporting

confidence: 69%

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

Nuche-Berenguer

Jensen

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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P-21-activated kinases(PAKs) are serine/threonine kinases comprising six isoforms divided in two groups, group-I(PAK1-3)/group-II(PAK4-6) which play important roles in cell cytoskeletal dynamics, survival, secretion and proliferation and are activated by diverse stimuli. However, little is known about PAKs ability to be activated by gastrointestinal(GI) hormones/neurotransmitters/growth-factors. We used rat pancreatic acini to explore the ability of GI- hormones/neurotransmitters/growth-factors to activate Group-I-PAKs and the signaling cascades involved. Only PAK2 was present in acini. PAK2 was activated by some pancreatic growth-factors[EGF, PDGF, bFGF], by secretagogues activating phospholipase-C(PLC) [CCK, carbachol, bombesin] and by post-receptor stimulants activating PKC[TPA], but not agents only mobilizing cellular calcium or increasing cyclic AMP. CCK-activation of PAK2 required both high- and low-affinity-CCK1-receptor-state activation. It was partially reduced by PKC- or Src-inhibition, but not with PI3K-inhibitors(wortmannin, LY294002) or thapsigargin. IPA-3, which prevents PAK2 binding to small-GTPases partially inhibited PAK2-activation, as well as reduced CCK-induced ERK1/2 activation and amylase release induced by CCK or bombesin. This study demonstrates pancreatic acini, possess only one Group-I-PAK, PAK2. CCK and other GI-hormones/neurotransmitters/growth-factors activate PAK2 via small GTPases(CDC42/Rac1), PKC and SFK but not cytosolic calcium or PI3K. CCK-activation of PAK2 showed several novel features being dependent on both receptor-activation states, having PLC-and PKC-dependent/independent components and small-GTPase-dependent/independent components. These results show PAK2 is important in signaling cascades activated by numerous pancreatic stimuli which mediate their various physiological/pathophysiological responses and thus could be a promising target for the development of therapies in some pancreatic disorders such as pancreatitis.

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Section: Discussionsupporting

confidence: 69%

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

Nuche-Berenguer

Jensen

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…12c). Previous study also showed that tyrosine kinase Yes, the closest member of Src among the Src family kinases (SFKs), is activated by glucose36. Consistently, add-back glucose induced Yes phosphorylation, but not Src and Fyn (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 60%

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis

Zhang

Rezaeian

et al. 2017

Nat Commun

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Dynamic changes in histone modifications under various physiological cues play important roles in gene transcription and cancer. Identification of new histone marks critical for cancer development is of particular importance. Here we show that, in a glucose-dependent manner, E3 ubiquitin ligase NEDD4 ubiquitinates histone H3 on lysine 23/36/37 residues, which specifically recruits histone acetyltransferase GCN5 for subsequent H3 acetylation. Genome-wide analysis of chromatin immunoprecipitation followed by sequencing reveals that NEDD4 regulates glucose-induced H3 K9 acetylation at transcription starting site and enhancer regions. Integrative analysis of ChIP-seq and microarray data sets also reveals a consistent role of NEDD4 in transcription activation and H3 K9 acetylation in response to glucose. Functionally, we show that NEDD4-mediated H3 ubiquitination, by transcriptionally activating IL1α, IL1β and GCLM, is important for tumour sphere formation. Together, our study reveals the mechanism for glucose-induced transcriptome reprograming and epigenetic regulation in cancer by inducing NEDD4-dependent H3 ubiquitination.

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“…Indeed, recent investigations by Yoder et al [28] provide compelling evidence for YES tyrosine kinase activation as an early signalling event (~1 min) involved in the activation of the small G protein Cdc42 (~3 min) in glucose-stimulated islet beta cell. Likewise, studies of Garrett et al have demonstrated a requirement for tyrosine phosphorylation of VAV2 in vascular endothelial growth factor-induced Rac1 activation in endothelial cells [44].…”

Section: Discussionmentioning

confidence: 99%

“…Several Src family tyrosine kinases (SFKs) such as Lck and Fyn [23, 24], Syk family tyrosine kinases (Syk and Zap70) [24, 25], and receptor tyrosine kinases [26, 27] have been implicated as mediators of VAV2 tyrosine phosphorylation. Recent studies have shown that activation of tyrosine-protein kinase Yes (an Src family kinase) is indispensable for Cdc42 activation in a glucose-specific manner in pancreatic beta cells [28]. The aim of the current study, therefore, was to understand the roles of VAV2 in islet function, including GSIS.…”

Section: Introductionmentioning

confidence: 99%

VAV2, a guanine nucleotide exchange factor for Rac1, regulates glucose-stimulated insulin secretion in pancreatic beta cells

et al. 2015

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Aims/hypothesis Rho GTPases (Ras-related C3 botulinum toxin substrate 1 [Rac1] and cell division cycle 42 [Cdc42]) have been shown to regulate glucose-stimulated insulin secretion (GSIS) via cytoskeletal remodelling, trafficking and fusion of insulin-secretory granules with the plasma membrane. GTP loading of these G proteins, which is facilitated by GDP/GTP exchange factors, is a requisite step in the regulation of downstream effector proteins. Guanine nucleotide exchange factor VAV2 (VAV2), a member of the Dbl family of proteins, has been identified as one of the GDP/GTP exchange factors for Rac1. Despite recent evidence on the regulatory roles of VAV2 in different cell types, roles of this guanine nucleotide exchange factor in the signalling events leading to GSIS remain undefined. Using immunological, short-interfering RNA (siRNA), pharmacological and microscopic approaches we investigated the role of VAV2 in GSIS from islet beta cells. Methods Co-localisation of Rac1 and VAV2 was determined by Triton X-114 phase partition and confocal microscopy. Glucose-induced actin remodelling was quantified by live cell imaging using the LifeAct-GFP fluorescent biosensor. Rac1 activation was determined by G protein linked immunosorbent assay (G-LISA). Results Western blotting indicated that VAV2 is expressed in INS-1 832/13 beta cells, normal rat islets and human islets. Vav2 siRNA markedly attenuated GSIS in INS-1 832/13 cells. Ehop-016, a newly discovered small molecule inhibitor of the VAV2–Rac1 interaction, or siRNA-mediated knockdown of VAV2 markedly attenuated glucose-induced Rac1 activation and GSIS in INS-1 832/13 cells. Pharmacological findings were recapitulated in primary rat islets. A high glucose concentration promoted co-localisation of Rac1 and VAV2. Real-time imaging in live cells indicated a significant inhibition of glucose-induced cortical actin remodelling by Ehop-016. Conclusions Our data provide the first evidence to implicate VAV2 in glucose-induced Rac1 activation, actin remodelling and GSIS in pancreatic beta cells.

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YES, a Src Family Kinase, Is a Proximal Glucose-specific Activator of Cell Division Cycle Control Protein 42 (Cdc42) in Pancreatic Islet β Cells

Cited by 37 publications

References 73 publications

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

H3 ubiquitination by NEDD4 regulates H3 acetylation and tumorigenesis

VAV2, a guanine nucleotide exchange factor for Rac1, regulates glucose-stimulated insulin secretion in pancreatic beta cells

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