ArticleBiochemical pharmacology2013
A p21-activated kinase (PAK1) signaling cascade coordinately regulates F-actin remodeling and insulin granule exocytosis in pancreatic β cells.
Article in Biochemical pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 73 citations in OpenAlex.
- DOCK10 Regulates Insulin Hypersecretion in Insulinoma and Serves as a Diagnostic and Therapeutic Target.Cellular and molecular gastroenterology and hepatology · 2026Article
- Heterogeneity in the coordination of delta cells with beta cells is driven by both paracrine signals and low-density Cx36 gap junctions.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- p21-Activated Kinase 1 (Pak1) as an Element in Functional and Dysfunctional Interplay Among the Myocardium, Adipose Tissue, and Pancreatic Beta Cells.Comprehensive Physiology · 2025Review
- Review
- TAS1R3 influences GTPase-dependent signaling in human islet β-cells.Frontiers in endocrinology · 2025Article
- Beta cell-specific PAK1 enrichment ameliorates diet-induced glucose intolerance in mice by promoting insulin biogenesis and minimising beta cell apoptosis.Diabetologia · 2025Article
- Cellular mechanisms of hormone secretion in neuroendocrine tumors: what goes wrong?Frontiers in cell and developmental biology · 2025Review
- CDC42 Regulatory Patterns Related To Inflammatory Bowel Disease and Hyperglycemia.Journal of bioinformatics and systems biology : Open access · 2025Article
- Article
- The Role of Cdc42 in the Insulin and Leptin Pathways Contributing to the Development of Age-Related Obesity.Nutrients · 2023Review
- Toward Ameliorating Insulin Resistance: Targeting a Novel PAK1 Signaling Pathway Required for Skeletal Muscle Mitochondrial Function.Antioxidants (Basel, Switzerland) · 2023Article
- Nutrient regulation of the islet epigenome controls adaptive insulin secretion.The Journal of clinical investigation · 2023Article
- GWAS in people of Middle Eastern descent reveals a locus protective of kidney function-a cross-sectional study.BMC medicine · 2022Article
- CARD9 mediates glucose-stimulated insulin secretion in pancreatic beta cells.Biochemical pharmacology · 2021Article
- Temporal coding of ERK signalling in β-cells.Nature reviews. Endocrinology · 2021Article
- A High-Content Screen for the Identification of Plant Extracts with Insulin Secretion-Modulating Activity.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Targeting Small GTPases and Their Prenylation in Diabetes Mellitus.Journal of medicinal chemistry · 2021Review
- Conventional and Unconventional Mechanisms by which Exocytosis Proteins Oversee β-cell Function and Protection.International journal of molecular sciences · 2021Review
- A requirement for PAK1 to support mitochondrial function and maintain cellular redox balance via electron transport chain proteins to prevent β-cell apoptosis.Metabolism: clinical and experimental · 2021Article
- Integrin and autocrine IGF2 pathways control fasting insulin secretion in β-cells.The Journal of biological chemistry · 2020Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Human islet studies implicate an important signaling role for the Cdc42 effector protein p21-activated kinase (PAK1) in the sustained/second-phase of insulin secretion. Because human islets from type 2 diabetic donors lack ∼80% of normal PAK1 protein levels, the mechanistic requirement for PAK1 signaling in islet function was interrogated. Similar to MIN6 β cells, human islets elicited glucose-stimulated PAK1 activation that was sensitive to the PAK1 inhibitor, IPA3. Given that sustained insulin secretion has been correlated with glucose-induced filamentous actin (F-actin) remodeling, we tested the hypothesis that a Cdc42-activated PAK1 signaling cascade is required to elicit F-actin remodeling to mobilize granules to the cell surface. Live-cell imaging captured the glucose-induced cortical F-actin remodeling in MIN6 β cells; IPA3-mediated inhibition of PAK1 abolished this remodeling. IPA3 also ablated glucose-stimulated insulin granule accumulation at the plasma membrane, consistent with its role in sustained/second-phase insulin release. Both IPA3 and a selective inhibitor of the Cdc42 GTPase, ML-141, blunted the glucose-stimulated activation of Raf-1, suggesting Raf-1 to be downstream of Cdc42→PAK1. IPA3 also inhibited MEK1/2 activation, implicating the MEK1/2→ERK1/2 cascade to occur downstream of PAK1. Importantly, PD0325901, a new selective inhibitor of MEK1/2→ERK1/2 activation, impaired F-actin remodeling and the sustained/amplification pathway of insulin release. Taken together, these data suggest that glucose-mediated activation of Cdc42 leads to activation of PAK1 and prompts activation of its downstream targets Raf-1, MEK1/2 and ERK1/2 to elicit F-actin remodeling and recruitment of insulin granules to the plasma membrane to support the sustained phase of insulin release.
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