Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling

Jean, Steve; Cox, Sarah; Schmidt, Edward M.; Robinson, Fred L.; Kiger, Amy A.

doi:10.1091/mbc.e12-05-0375

Cited by 65 publications

(104 citation statements)

References 76 publications

(79 reference statements)

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“…PIP5K1C90 likely traffics through EEA1-positive endosomes and emerges largely in RAB21-positive recycling vesicles. GTP-bound RAB21 exits from the endosomes (Jean et al, 2012) and preferentially recruits phosphorylated RHP3A as PKN1-mediated RPH3A phosphorylation enhances RPH3A interaction with RAB21. We believe that the interaction has an important role in transport of RAB21-vesicles carrying PIP5K1C90 from endosomes to its polarized destination on the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury

Yuan

Ren

et al. 2017

Cell Reports

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SUMMARY Polarized vesicle transport plays an important role in cell polarization, but the mechanisms underlying this process and its role in innate immune responses are not well understood. Here, we describe a phosphorylation-regulated polarization mechanism that is important for neutrophil adhesion to endothelial cells during inflammatory responses. We show that the protein kinase PKN1 phosphorylates RPH3A, which enhances binding of RPH3A to GTP-bound RAB21. These interactions are important for polarized localization of RAB21 and RPH3A in neutrophils, which leads to PIP5K1C90 polarization. Consistent with the roles of PIP5K1C90 polarization, the lack of PKN1 or RPH3A impairs neutrophil integrin activation, adhesion to endothelial cells, and infiltration in inflammatory models. Furthermore, myeloid-specific loss of PKN1 decreases tissue injury in a renal ischemia-reperfusion model. Thus, this study characterizes a mechanism for protein polarization in neutrophils and identifies a potential protein kinase target for therapeutic intervention in reperfusion-related tissue injury.

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Section: Discussionmentioning

confidence: 99%

PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury

Yuan

Ren

et al. 2017

Cell Reports

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“…8 The class II PI3K homolog in flies regulates endosomal sorting from the endocytic compartment to the plasma membrane. 37,38 Thus, PI3K-C2a is a central spatiotemporal player of membrane dynamics by acting at several levels, including membrane skeleton organization, clathrin-dependent endocytosis, and endocytic recycling.…”

Section: Discussionmentioning

confidence: 99%

Essential role of class II PI3K-C2α in platelet membrane morphology

Valet

Chicanne

Severac

et al. 2015

Blood

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Key Points• PI3K-C2a controls platelet membrane structure and remodeling.• PI3K-C2a is a key regulator of a basal housekeeping PI3P pool in platelets.The physiologic roles of the class II phosphoinositide 3-kinases (PI3Ks) and their contributions to phosphatidylinositol 3-monophosphate (PI3P) and PI(3,4)P 2 production remain elusive. Here we report that mice heterozygous for a constitutively kinase-dead PI3K-C2a display aberrant platelet morphology with an elevated number of barbell-shaped proplatelets, a recently discovered intermediate stage in the final process of platelet production. Platelets with heterozygous PI3K-C2a inactivation have critical defects in a-granules and membrane structure that are associated with modifications in megakaryocytes. These platelets are more rigid and unable to form filopodia after stimulation. Heterozygous PI3K-C2a inactivation in platelets led to a significant reduction in the basal pool of PI3P and a mislocalization of several membrane skeleton proteins known to control the interactions between the plasma membrane and cytoskeleton. These alterations had repercussions on the performance of platelet responses with delay in the time of arterial occlusion in an in vivo model of thrombosis and defect in thrombus formation in an ex vivo blood flow system. These data uncover a key role for PI3K-C2a activity in the generation of a basal housekeeping PI3P pool and in the control of membrane remodeling, critical for megakaryocytopoiesis and normal platelet production and function. (Blood. 2015;126(9):1128-1137

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“…Binding of MTM1 or MTMR2 to the regulatory subunit of Vps34, Vps15, is crucial for their localization to early and late endosomes, respectively, and regulates PI 3-kinase as well as PI 3-phosphatase activity (Cao, Backer et al 2008). Furthermore, Sbf2, the Drosophila homologue of the pseudo-phosphatase MTMR13, is required for membrane localization of the class II PI3K Pi3K68D and mtm, homologues to mammalian MTM1, MTMR1 and MTMR2 (Jean, Cox et al 2012). Thus, recruitment of myotubularins by PI 3-kinases might be required for locally and temporally restricted PI(3)P turnover while maintaining the overall, endosomal PI(3)P content.…”

Section: Membrane Recruitment Of Mtm1 Is Regulated By Lipid and Protementioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

157

173

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I owe special thanks to Marnix Wieffer and Michael Krauß, who spent a lot of time helping me to get started in the lab, to overcome numerous experimental problem, I was not sure how to deal with, and frequently joined in discussions about my project with excellent advice. I am really grateful for your experimental support, Michael, and the time you invested in the project during our paper revision.Further, I would like to thank Jocelyn Laporte and his group, especially Anne-Sophie Nicot, at the IGBMC in Strasbourg for their support and a very fruitful collaboration, and Carsten Schultz and his group at the EMBL in Heidelberg for their support and constant supply with PIP/AMs. I owe special thanks to Dmytro Puchkov for the ultrastructural analysis and Eberhard Krause for mass spectrometry done within this project. I also need to acknowledge Markus Wenk and Federico Torta at the Singapore Lipidomics Incubator for joining the project at a very late stage, when we urgently needed help from lipidomics specialists. It was a pity that experiments did not work out as planned.I would further like to express my gratitude to two very skilled technicians in the AG Haucke lab: Silke Zillmann and Delia Löwe. Without your help it would have been impossible to achieve so much within the limited amount of time I had during the paper revision. by VPS34-IN1 treatment................................................... 52 2.3.11 Fluorescence microscopy................................................................................. 53 2.3.12 Flow cytometry............................................................................................ III SummaryPhosphoinositides (PIs) are a minor class of short-lived phospholipids that serve as crucial signposts of membrane identity. Thereby, PIs full fill important functions in cell signaling and membrane transport. PI 4-phosphates such as phosphatitylinositol-4-phosphate (PI(4)P) and phosphatitylinositol-4,5-bisphosphate (PI(4,5)P 2 ) are enriched at the plasma membrane (PM), on secretory organelles and lysosomes, while PI 3-phosphates, i.e.phosphatitylinositol-3-phosphate (PI(3)P), are a hallmark of the endosomal system.Directional transport between these compartments, thus, requires regulated PI conversion.However, PI conversion in exit from PI(3)P-enriched endosomes en route to the PI(4)P-and PI(4,5)P 2 -positive PM in endosomal recycling remained unknown.Here, we report that cargo exit from endosomes requires removal of PI(3)P by the PI(3)P 3-phosphatase myotubularin 1 (MTM1), and concomitant PI(4)P synthesis by PI 4-kinase type II α (PI4K2α). Loss of MTM1 causes endosomal accumulation of PI(3)P and PI(3)P effector proteins, i.e. sorting nexins, Kif16b-mediated outward traffic of PI(3)P containing endosomes and sub-plasmalemmal accumulation of exocytosis-deficient endosomes. As PI4K2α associates with MTM1 and thereby facilitates membrane recruitment of MTM1, these phenotypic changes are mimicked by loss of PI4K2α. The conversion of PI(3)P-to-PI(4)P is paralleled by a switch i...

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Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling

Cited by 65 publications

References 76 publications

PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury

PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury

Essential role of class II PI3K-C2α in platelet membrane morphology

A phosphoinositide conversion mechanism for exit from endosomes

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