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题名:A p21-activated kinase (PAK1) signaling cascade coordinately regulates F-actin remodeling and insulin granule exocytosis in pancreatic beta cells.
作者:KALWAT MA; YODER SM; WANG Z; THURMOND DC;
来源:Biochem Pharmacol. 2013 Mar 15;85(6):808-16. doi: 10.1016/j.bcp.2012.12.003. Epub [ IF= 0.00 ] ]
URL :10.1016/j.bcp.2012.12.003
日期:20130330
摘要: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 approximately
80% of normal PAK1 protein levels, the mechanistic requirement for PAK1 signaling
in islet function was interrogated. Similar to MIN6 beta 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 beta 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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