Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

Abstract

Background: P21-activated kinase (PAK1) is a downstream effector of the GTPase Cdc42. Results: Inhibition of Cdc42-PAK1 signaling in human islets inhibited insulin secretion. PAK1 knock-out mice showed defects in insulin release and skeletal muscle insulin action, underlying impaired whole body glucose homeostasis. Conclusion: Attenuated PAK1 abundance/activation may contribute to type 2 diabetes susceptibility. Significance: Cdc42-PAK1 signaling is crucial for regulating glucose homeostasis in vivo.

Actin Dynamics Regulated by the Balance of Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP) and Cofilin Activities Determines the Biphasic Response of Glucose-induced Insulin Secretion

“…Indeed, introduction of an N-WASP DN into MIN6-K8 ␤-cells or N-WASP knockdown disclosed a marked decrease of the second phase of GIIS, as assessed by perifusion experiments. These findings are consistent with the recent studies showing that the second phase of GIIS was decreased in perifused Cdc42 knockdown islets and islets isolated from PAK1 knock-out mice (13,58). A cofilin DN is known to inhibit the supply of G-actin that is essential for actin polymerization by blocking endogenous cofilin (50).…”

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

“…In support of this idea, human islets of patients with T2D exhibit a strong decrease (80% less than controls) in P21-activated kinase PAK1, a downstream effector of Cdc42 and RAC1 signaling that controls cytoskeletal remodeling. Furthermore, PAK1 inhibition in nondiabetic islets leads to a selective reduction of the second phase of GSIS (15). Finally, diabetic islets from humans with T2D (82) contained ~10 times higher levels of total actin than controls, and a similar higher level of actin has also been reported in Goto-Kakizaki rats (83,84).…”

“…The selective reduction of the second phase of GSIS in Dnm2 KO mice shows striking parallel with the reduced insulin secretion after perturbations of actin remodeling (13)(14)(15)81), a key factor that selectively contributes to the second phase (10,11). Accordingly, enhanced actin disassembly by PPARβ/δ (17) or the actin-capping protein gelsolin (81) increases the second phase.…”

“…Moreover, increasing evidence supports an emerging model in which the actin cytoskeleton plays a critical role in biphasic GSIS (10,11) through granule mobilization and recruitment from the reserve pool to the PM. Many actin remodeling molecules, such as the Rho GTPase family proteins Cdc42 (13) and RAC1 (14), PAK1 (15), N-WASP (16), and PPARβ/δ (17), selectively regulate the second phase of GSIS, and perturbations of microtubules (18) and kinesin-1 (19) disrupt the second phase.…”

Expansion of BCR/ABL1+ cells requires PAK2 but not PAK1

“…However, knockout mice revealed distinct functions for either kinase. Upon loss of PAK1, mice display reduced mast cell degranulation and disturbed glucose homeostasis (Allen et al , 2009; Wang et al , 2011; Rane & Minden, 2014). Mice deficient for PAK2 die on embryonic day E8.5 due to defects in endothelial development (Hofmann et al , 2004; Radu et al , 2015).…”