A Network of Interactions Enables CCM3 and STK24 to Coordinate UNC13D-Driven Vesicle Exocytosis in Neutrophils

Zhang, Yong; Tang, Wenwen; Zhang, Haifeng; Niu, Xiaofeng; Xu, Yingke; Zhang, Jiasheng; Gao, Kun; Pan, Weijun; Boggon, Titus J.; Toomre, Derek; Wang, Min; Wu, Dianqing

doi:10.1016/j.devcel.2013.09.021

Cited by 64 publications

(79 citation statements)

References 63 publications

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“…In neutrophils, for example, CCM3 promotes exocytosis through the small GTPase Rab27 (ref. 64). In summation, it is becoming clear that CCM3 regulates multiple trafficking events, many of which are likely to be cell-type specific.…”

Section: Discussionmentioning

confidence: 99%

CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling

et al. 2015

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The mechanisms governing apical membrane assembly during biological tube development are poorly understood. Here, we show that extension of the C. elegans excretory canal requires cerebral cavernous malformation 3 (CCM-3), independent of the CCM1 orthologue KRI-1. Loss of ccm-3 causes canal truncations and aggregations of canaliculular vesicles, which form ectopic lumen (cysts). We show that CCM-3 localizes to the apical membrane, and in cooperation with GCK-1 and STRIPAK, promotes CDC-42 signalling, Golgi stability and endocytic recycling. We propose that endocytic recycling is mediated through the CDC-42-binding kinase MRCK-1, which interacts physically with CCM-3-STRIPAK. We further show canal membrane integrity to be dependent on the exocyst complex and the actin cytoskeleton. This work reveals novel in vivo roles of CCM-3 Á STRIPAK in regulating tube extension and membrane integrity through small GTPase signalling and vesicle dynamics, which may help explain the severity of CCM3 mutations in patients.

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Section: Discussionmentioning

confidence: 99%

CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling

et al. 2015

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“…The chemotaxis assay using a Dunn chamber was carried out as previously described (37), with some modifications (34,38). Both WT and Ubl4A-deficient neutrophils were simultaneously labeled with different tracing dyes.…”

Section: Methodsmentioning

confidence: 99%

Ubl4A is required for insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching

Zhao

Lin

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The serine-threonine kinase Akt is a key regulator of cell proliferation and survival, glucose metabolism, cell mobility, and tumorigenesis. Activation of Akt by extracellular stimuli such as insulin centers on the interaction of Akt with PIP3 on the plasma membrane, where it is subsequently phosphorylated and activated by upstream protein kinases. However, it is not known how Akt is recruited to the plasma membrane upon stimulation. Here we report that ubiquitin-like protein 4A (Ubl4A) plays a crucial role in insulin-induced Akt plasma membrane translocation. Ubl4A knockout newborn mice have defective Akt-dependent glycogen synthesis and increased neonatal mortality. Loss of Ubl4A results in the impairment of insulin-induced Akt translocation to the plasma membrane and activation. Akt binds actin-filaments and colocalizes with actin-related protein 2 and 3 (Arp2/3) complex in the membrane ruffles and lamellipodia. Ubl4A directly interacts with Arp2/3 to accelerate actin branching and networking, allowing Akt to be in close proximity to the plasma membrane for activation upon insulin stimulation. Our finding reveals a new mechanism by which Akt is recruited to the plasma membrane for activation, thereby providing a missing link in Akt signaling.

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“…Mouse neutrophils were purified from bone marrow as previously described (Tang et al, 2011;Xu et al, 2010;Zhang et al, 2013). Briefly, bone marrow cells collected from mice were treated with ACK buffer (155 mM NH 4 Cl, 10 mM KHCO 3 and 127 mM EDTA) for red blood cell lysis, followed by a discontinuous Percoll density gradient centrifugation.…”

Section: Neutrophil Preparation Transfection and Stainingmentioning

confidence: 99%

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

Gao

Tang

et al. 2015

Journal of Cell Science

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A hallmark of neutrophil polarization is the back localization of active RHOA and phosphorylated myosin light chain (pMLC, also known as MYL2). However, the mechanism for the polarization is not entirely clear. Here, we show that FAM65B, a newly identified RHOA inhibitor, is important for the polarization. When FAM65B is phosphorylated, it binds to 14-3-3 family proteins and becomes more stable. In neutrophils, chemoattractants stimulate FAM65B phosphorylation largely depending on the signals from the front of the cells that include those mediated by phospholipase Cb (PLCb) and phosphoinositide 3-kinase c (PI3Kc), leading to FAM65B accumulation at the leading edge. Concordantly, FAM65B deficiency in neutrophils resulted in an increase in RHOA activity and localization of pMLC to the front of cells, as well as defects in chemotaxis directionality and adhesion to endothelial cells under flow. These data together elucidate a mechanism for RHOA and pMLC polarization in stimulated neutrophils through direct inhibition of RHOA by FAM65B at the leading edge.

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A Network of Interactions Enables CCM3 and STK24 to Coordinate UNC13D-Driven Vesicle Exocytosis in Neutrophils

Cited by 64 publications

References 63 publications

CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling

CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling

Ubl4A is required for insulin-induced Akt plasma membrane translocation through promotion of Arp2/3-dependent actin branching

Front Signal-Dependent Accumulation of RHOA Inhibitor FAM65B at Leading Edges Polarizes Neutrophils

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