Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression

Dozynkiewicz, Marta Anna; Jamieson, Nigel B.; Macpherson, Iain; Grindlay, Joan; Berghe, Peter V. E. van den; Thun, Anne von; Morton, Jennifer P.; Gourley, Charlie; Timpson, Paul; Nixon, Colin; McKay, Colin; Carter, Ross; Strachan, David; Anderson, Kurt I.; Sansom, Owen J.; Caswell, Patrick T.; Norman, Jim C.

doi:10.1016/j.devcel.2011.11.008

Cited by 293 publications

(347 citation statements)

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“…Thus, it is essential for their recycling and thereby prevents degradative sorting (Bottcher, Stremmel et al 2012;Steinberg, Heesom et al 2012). However, loss of SNX17 and upregulation of the Rab11-like GTPase Rab25 leads to the sorting of active-conformation and ligand-occupied integrins to late endosomes (Dozynkiewicz, Jamieson et al 2012). Late endosomal enrichment of chloride intracellular channel 3 (CLIC3) prevents integrin degradation, presumably by interfering with inward budding from the limiting membrane and ILV generation, or by interfering with ubiquitylation.…”

Section: Late Endosomal Recycling Contributes To β1-integrin Trafficmentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

165

177

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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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Section: Late Endosomal Recycling Contributes To β1-integrin Trafficmentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

165

177

View full text Add to dashboard Cite

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“…The Rab11 family protein Rab25 (Rab11c) is associated with aggressive cancers (Cheng et al, 2004;Caswell et al, 2007;Goldenring and Nam, 2011). The regulation of α5β1 integrin transport by Rab25 has been identified as the critical function of Rab25 in cancer progression (Caswell et al, 2007;Dozynkiewicz et al, 2012). The transmembrane proteins of the integrin family connect cells to the extracellular matrix and are key functions in cell migration.…”

Section: Spir/fmn Dysfunction and Human Diseasementioning

confidence: 99%

Structural and functional insights into the Spir/formin actin nucleator complex

Dietrich

Weiß

Pleiser

et al. 2013

Biological Chemistry

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Abstract:The diversity of cellular actin functions is attained by the activation of actin nucleator complexes, which initiate the polymerization of actin monomers into a helical double-stranded filament at defined subcellular compartments. Next to actin functions at the cell membrane, including different forms of membrane protrusions and invaginations, actin dynamics at intracellular membranes has recently become a research focus. Experiments addressing the vesicle-associated Spir WH2 domain containing actin nucleators have provided novel mechanistic insights into the function of actin dynamics at intracellular membranes. Spir proteins are targeted by a modified FYVE zinc finger motif toward endosomal and vesicle membranes, where they interact and cooperate with the distinct nucleators of the FMN subfamily of formins in the nucleation of actin filaments. The function of the Spir/ formin actin nucleator complex is closely related to the Rab11 small G protein, which is a key regulator of recycling and exocytic transport processes. Together with the actin motor protein and Rab11 effector myosin Vb, Spir/ formin nucleated actin filaments mediate actin-dependent vesicle transport processes. Drosophila and mouse genetic studies as well as cell biology experiments point toward an important role of the Spir/formin complex in oocyte maturation and in the structure and signaling of the nervous system.

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“…Although Rab13 has been found on both recycling and late endosomes, TI-VAMP mediates an exocytic pathway originating from late endosomes (86). Indeed, integrin recycling from late endosomes drives cancer cell invasion and metastasis (87). Enhanced integrin trafficking observed in p53 gain-of-function mutants also depends on the activity of diacylglycerol kinase ␣ to tether Rab-coupling protein (RCP) to the tips of invasive protrusions (33,88).…”

Section: Cell Migration and Scatteringmentioning

confidence: 99%

Regulation of Cancer Cell Behavior by the Small GTPase Rab13

Ioannou

McPherson

2016

Journal of Biological Chemistry

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The members of the Rab family of GTPases are master regulators of cellular membrane trafficking. With ϳ70 members in humans, Rabs have been implicated in all steps of membrane trafficking ranging from vesicle formation and transport to vesicle docking/tethering and fusion. Vesicle trafficking controls the localization and levels of a myriad of proteins, thus regulating cellular functions including proliferation, metabolism, cellcell adhesion, and cell migration. It is therefore not surprising that impairment of Rab pathways is associated with diseases including cancer. In this review, we highlight evidence supporting the role of Rab13 as a potent driver of cancer progression.The members of the Rab (Ras-related in brain) family of proteins are master regulators of vesicle trafficking. They are evolutionarily conserved with ϳ70 members in humans, and each Rab is localized predominantly to a specific intracellular organelle or vesicle (1). Rabs have been implicated in every step of vesicle trafficking including the formation of cargo-laden membrane vesicles and tubules, transport of these carriers on the cytoskeleton, tethering and docking of the carriers at the target membrane, and finally membrane fusion and delivery of cargo. Not surprisingly, functional impairment of Rab pathways is associated with diseases including immunodeficiencies, neurological disorders, and cancer (2). One such Rab, Rab13, controls cellular functions that are often altered in cancer, and Rab13 is now recognized as an important driver of cancer progression. Here, we discuss the importance of Rab13 in the physiology of cancer with a focus on Rab13 trafficking pathways contributing to tumorigenicity. The Biology of Rab13As for all small GTPases, Rab13 cycles between an active, GTP-bound state and an inactive, GDP-bound state. Activation of Rab13 is mediated by DENND2B and DENND1C/connecdenn 3, guanine nucleotide exchange factors (GEFs) 2 that interact with GDP-bound Rab13 and facilitate the exchange of GDP for GTP (3-5). These proteins each bear a differentially expressed in normal and neoplastic cells (DENN) domain, an evolutionarily ancient protein module that encodes GEF activity for a large number of Rab GTPases (6 -8). Rab13 is inactivated by the GTPase-activating protein (GAP) Akt substrate 160 (AS160)/TBC1D4, which enhances the ability of Rab13 to hydrolyze GTP (3-5). In its active form, Rab13 binds to several effectors including MICAL-L1, MICAL-L2, and PKA (9, 10). Rab13, which is ubiquitously expressed, is thought to have diverged from its closest homologue Rab8, early in the vertebrate lineage (11). Similar to Rab8, Rab13 has been implicated in both biosynthetic and endosomal recycling pathways. Rab13 is found at the trans-Golgi network, on recycling endosomes, on late endosomes, and at the plasma membrane (12-14). Disruption of Rab13 function inhibits the delivery of cargo that reaches the plasma membrane via endosomes from either the biosynthetic or the endocytic recycling pathways. Thus, Rab13 is thought to control membrane t...

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Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression

Cited by 293 publications

References 33 publications

A phosphoinositide conversion mechanism for exit from endosomes

A phosphoinositide conversion mechanism for exit from endosomes

Structural and functional insights into the Spir/formin actin nucleator complex

Regulation of Cancer Cell Behavior by the Small GTPase Rab13

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