Rittmeyer Eric N, Daniel Samira, Hsu Shu-Chan, Osman Mahasin A
Department of Microbiology, Cornell University, Ithaca, NY 14853-2703, USA.
J Cell Sci. 2008 Feb 1;121(Pt 3):391-403. doi: 10.1242/jcs.016881.
Polarized secretion is a tightly regulated event generated by conserved, asymmetrically localized multiprotein complexes, and the mechanism(s) underlying its temporal and spatial regulation are only beginning to emerge. Although yeast Iqg1p has been identified as a positional marker linking polarity and exocytosis cues, studies on its mammalian counterpart, IQGAP1, have focused on its role in organizing cytoskeletal architecture, for which the underlying mechanism is unclear. Here, we report that IQGAP1 associates and co-localizes with the exocyst-septin complex, and influences the localization of the exocyst and the organization of septin. We further show that activation of CDC42 GTPase abolishes this association and inhibits secretion in pancreatic beta-cells. Whereas the N-terminus of IQGAP1 binds the exocyst-septin complex, enhances secretion and abrogates the inhibition caused by CDC42 or the depletion of IQGAP1, the C-terminus, which binds CDC42, inhibits secretion. Pulse-chase experiments indicate that IQGAP1 influences protein-synthesis rates, thus regulating exocytosis. We propose and discuss a model in which IQGAP1 serves as a conformational switch to regulate exocytosis.
极化分泌是由保守的、不对称定位的多蛋白复合物产生的一个受到严格调控的过程，其时间和空间调控的潜在机制才刚刚开始显现。尽管酵母Iqg1p已被鉴定为连接极性和胞吐作用线索的位置标记，但对其哺乳动物对应物IQGAP1的研究主要集中在其在组织细胞骨架结构中的作用，其潜在机制尚不清楚。在这里，我们报告IQGAP1与外被体- septin复合物相关联并共定位，并影响外被体的定位和septin的组织。我们进一步表明，CDC42 GTP酶的激活消除了这种关联，并抑制胰腺β细胞中的分泌。IQGAP1的N末端结合外被体- septin复合物，增强分泌并消除由CDC42或IQGAP1缺失引起的抑制作用，而结合CDC42的C末端则抑制分泌。脉冲追踪实验表明，IQGAP1影响蛋白质合成速率，从而调节胞吐作用。我们提出并讨论了一个模型，其中IQGAP1作为一个构象开关来调节胞吐作用。
