Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo

Zhanxiang Wang, Eunjin Oh, D. Clapp, Jonathan Chernoff, Debbie C. Thurmond

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

The p21-activated kinase PAK1 is implicated in tumorigenesis, and efforts to inhibit PAK1 signaling as a means to induce tumor cell apoptosis are underway. However, PAK1 has also been implicated as a positive effector of mechanisms in clonal pancreatic beta cells and skeletal myotubes that would be crucial to maintaining glucose homeostasis in vivo. Of relevance, human islets of Type 2 diabetic donors contained ∼80% less PAK1 protein compared with non-diabetics, implicating PAK1 in islet signaling/scaffolding functions. Mimicking this, islets from PAK1 -/- knock-out mice exhibited profound defects in the second/sustained-phase of insulin secretion. Reiteration of this specific defect by human islets treated with the PAK1 signaling inhibitor IPA3 revealed PAK1 signaling to be of primary functional importance. Analyses of human and mouse islet beta cell signaling revealed PAK1 activation to be 1) dependent upon Cdc42 abundance, 2) crucial for signaling downstream to activate ERK1/2, but 3) dispensable for cofilin phosphorylation. Importantly, the PAK1 -/- knock-out mice were found to exhibit whole body glucose intolerance in vivo. Exacerbating this, the PAK1 -/- knock-out mice also exhibited peripheral insulin resistance. Insulin resistance was coupled to ablation of insulin-stimulated GLUT4 translocation in skeletal muscle from PAK1 -/- knock-out mice, and in sharp contrast to islet beta cells, skeletal muscle PAK1 loss was underscored by defective cofilin phosphorylation but normal ERK1/2 activation. Taken together, these data provide the first human islet and mammalian in vivo data unveiling the key and crucial roles for differential PAK1 signaling in the multi-tissue regulation of whole body glucose homeostasis.

Original languageEnglish
Pages (from-to)41359-41367
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number48
DOIs
StatePublished - Dec 2 2011

Fingerprint

p21-Activated Kinases
Ablation
Knockout Mice
Actin Depolymerizing Factors
Glucose
Islets of Langerhans
Insulin
Insulin Resistance
Phosphorylation
Skeletal Muscle
Homeostasis
Glucose Intolerance
Muscle
Skeletal Muscle Fibers
Insulin-Secreting Cells
Chemical activation
Vascular Resistance
Cell signaling
Defects
Carcinogenesis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo. / Wang, Zhanxiang; Oh, Eunjin; Clapp, D.; Chernoff, Jonathan; Thurmond, Debbie C.

In: Journal of Biological Chemistry, Vol. 286, No. 48, 02.12.2011, p. 41359-41367.

Research output: Contribution to journalArticle

Wang, Zhanxiang ; Oh, Eunjin ; Clapp, D. ; Chernoff, Jonathan ; Thurmond, Debbie C. / Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 48. pp. 41359-41367.
@article{60a6f68e1f76431585a93a4ab27c859a,
title = "Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo",
abstract = "The p21-activated kinase PAK1 is implicated in tumorigenesis, and efforts to inhibit PAK1 signaling as a means to induce tumor cell apoptosis are underway. However, PAK1 has also been implicated as a positive effector of mechanisms in clonal pancreatic beta cells and skeletal myotubes that would be crucial to maintaining glucose homeostasis in vivo. Of relevance, human islets of Type 2 diabetic donors contained ∼80{\%} less PAK1 protein compared with non-diabetics, implicating PAK1 in islet signaling/scaffolding functions. Mimicking this, islets from PAK1 -/- knock-out mice exhibited profound defects in the second/sustained-phase of insulin secretion. Reiteration of this specific defect by human islets treated with the PAK1 signaling inhibitor IPA3 revealed PAK1 signaling to be of primary functional importance. Analyses of human and mouse islet beta cell signaling revealed PAK1 activation to be 1) dependent upon Cdc42 abundance, 2) crucial for signaling downstream to activate ERK1/2, but 3) dispensable for cofilin phosphorylation. Importantly, the PAK1 -/- knock-out mice were found to exhibit whole body glucose intolerance in vivo. Exacerbating this, the PAK1 -/- knock-out mice also exhibited peripheral insulin resistance. Insulin resistance was coupled to ablation of insulin-stimulated GLUT4 translocation in skeletal muscle from PAK1 -/- knock-out mice, and in sharp contrast to islet beta cells, skeletal muscle PAK1 loss was underscored by defective cofilin phosphorylation but normal ERK1/2 activation. Taken together, these data provide the first human islet and mammalian in vivo data unveiling the key and crucial roles for differential PAK1 signaling in the multi-tissue regulation of whole body glucose homeostasis.",
author = "Zhanxiang Wang and Eunjin Oh and D. Clapp and Jonathan Chernoff and Thurmond, {Debbie C.}",
year = "2011",
month = "12",
day = "2",
doi = "10.1074/jbc.M111.291500",
language = "English",
volume = "286",
pages = "41359--41367",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "48",

}

TY - JOUR

T1 - Inhibition or ablation of p21-activated kinase (PAK1) disrupts glucose homeostatic mechanisms in vivo

AU - Wang, Zhanxiang

AU - Oh, Eunjin

AU - Clapp, D.

AU - Chernoff, Jonathan

AU - Thurmond, Debbie C.

PY - 2011/12/2

Y1 - 2011/12/2

N2 - The p21-activated kinase PAK1 is implicated in tumorigenesis, and efforts to inhibit PAK1 signaling as a means to induce tumor cell apoptosis are underway. However, PAK1 has also been implicated as a positive effector of mechanisms in clonal pancreatic beta cells and skeletal myotubes that would be crucial to maintaining glucose homeostasis in vivo. Of relevance, human islets of Type 2 diabetic donors contained ∼80% less PAK1 protein compared with non-diabetics, implicating PAK1 in islet signaling/scaffolding functions. Mimicking this, islets from PAK1 -/- knock-out mice exhibited profound defects in the second/sustained-phase of insulin secretion. Reiteration of this specific defect by human islets treated with the PAK1 signaling inhibitor IPA3 revealed PAK1 signaling to be of primary functional importance. Analyses of human and mouse islet beta cell signaling revealed PAK1 activation to be 1) dependent upon Cdc42 abundance, 2) crucial for signaling downstream to activate ERK1/2, but 3) dispensable for cofilin phosphorylation. Importantly, the PAK1 -/- knock-out mice were found to exhibit whole body glucose intolerance in vivo. Exacerbating this, the PAK1 -/- knock-out mice also exhibited peripheral insulin resistance. Insulin resistance was coupled to ablation of insulin-stimulated GLUT4 translocation in skeletal muscle from PAK1 -/- knock-out mice, and in sharp contrast to islet beta cells, skeletal muscle PAK1 loss was underscored by defective cofilin phosphorylation but normal ERK1/2 activation. Taken together, these data provide the first human islet and mammalian in vivo data unveiling the key and crucial roles for differential PAK1 signaling in the multi-tissue regulation of whole body glucose homeostasis.

AB - The p21-activated kinase PAK1 is implicated in tumorigenesis, and efforts to inhibit PAK1 signaling as a means to induce tumor cell apoptosis are underway. However, PAK1 has also been implicated as a positive effector of mechanisms in clonal pancreatic beta cells and skeletal myotubes that would be crucial to maintaining glucose homeostasis in vivo. Of relevance, human islets of Type 2 diabetic donors contained ∼80% less PAK1 protein compared with non-diabetics, implicating PAK1 in islet signaling/scaffolding functions. Mimicking this, islets from PAK1 -/- knock-out mice exhibited profound defects in the second/sustained-phase of insulin secretion. Reiteration of this specific defect by human islets treated with the PAK1 signaling inhibitor IPA3 revealed PAK1 signaling to be of primary functional importance. Analyses of human and mouse islet beta cell signaling revealed PAK1 activation to be 1) dependent upon Cdc42 abundance, 2) crucial for signaling downstream to activate ERK1/2, but 3) dispensable for cofilin phosphorylation. Importantly, the PAK1 -/- knock-out mice were found to exhibit whole body glucose intolerance in vivo. Exacerbating this, the PAK1 -/- knock-out mice also exhibited peripheral insulin resistance. Insulin resistance was coupled to ablation of insulin-stimulated GLUT4 translocation in skeletal muscle from PAK1 -/- knock-out mice, and in sharp contrast to islet beta cells, skeletal muscle PAK1 loss was underscored by defective cofilin phosphorylation but normal ERK1/2 activation. Taken together, these data provide the first human islet and mammalian in vivo data unveiling the key and crucial roles for differential PAK1 signaling in the multi-tissue regulation of whole body glucose homeostasis.

UR - http://www.scopus.com/inward/record.url?scp=82355184464&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=82355184464&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.291500

DO - 10.1074/jbc.M111.291500

M3 - Article

C2 - 21969371

AN - SCOPUS:82355184464

VL - 286

SP - 41359

EP - 41367

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 48

ER -