Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration

Rainero, Elena; Caswell, Patrick T.; Müller, Patricia; Grindlay, Joan; McCaffrey, Mary W.; Zhang, Zuo‐Feng; Wakelam, Michael J.O.; Vousden, Karen H.; Graziani, Andrea; Norman, Jim C.

doi:10.1083/jcb.201109112

Cited by 114 publications

(124 citation statements)

References 44 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…58 In breast carcinoma cells, DGKα-mediated PA generation mediates integrin recycling at the tips of invasive pseudopodial structures during invasive migration. 59 Additional studies are needed to determine whether DGKα-generated PA and/or its DAG consumption are necessary for MVB polarization to the IS.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

View full text Add to dashboard Cite

Multivesicular bodies (MVBs) are endocytic compartments that enclose intraluminal vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, these ILV contain Fas ligand (FasL) and are secreted as 'lethal exosomes' following activation-induced fusion of the MVB with the plasma membrane. Diacylglycerol (DAG) and diacylglycerol kinase α (DGKα) regulate MVB maturation and polarized traffic, as well as subsequent secretion of pro-apoptotic exosomes, but the molecular basis underlying these phenomena remains unclear. Here we identify protein kinase D (PKD) family members as DAG effectors involved in MVB genesis and secretion. We show that the inducible secretion of exosomes is enhanced when a constitutively active PKD1 mutant is expressed in T lymphocytes, whereas exosome secretion is impaired in PKD2-deficient mouse T lymphoblasts and in PKD1/3-null B cells. Analysis of PKD2-deficient T lymphoblasts showed the presence of large, immature MVB-like vesicles and demonstrated defects in cytotoxic activity and in activation-induced cell death. Using pharmacological and genetic tools, we show that DGKα regulates PKD1/2 subcellular localization and activation. Our studies demonstrate that PKD1/2 is a key regulator of MVB maturation and exosome secretion, and constitutes a mediator of the DGKα effect on MVB secretory traffic. Exosomes are nanovesicles that form as intraluminal vesicles (ILVs) inside multivesicular bodies (MVBs) and are then secreted by numerous cell types. 1 ILVs are generated by inward budding of late endosome limiting membrane in a precisely regulated maturation process. 2,3 Two main pathways are involved in MVB maturation. 4,5 In addition to the ESCRT (endosomal complex required for traffic) proteins, 6 there is increasing evidence that lipids such as lyso-bisphosphatidic acid (LBPA), 7 ceramides 8 and diacylglycerol (DAG) 9 contribute to this membrane invagination process.Exosomes participate in many biological processes related to T-cell receptor (TCR)-triggered immune responses, including T lymphocyte-mediated cytotoxicity and activationinduced cell death (AICD), antigen presentation and intercellular miRNA exchange. [10][11][12][13][14][15] The discovery of exosome involvement in these responses increased interest in the regulation of exosome biogenesis and secretory traffic, with special attention to the contribution of lipids such as ceramide and DAG, as well as DAG-binding proteins. 14,16-21 These studies suggest that positive and negative DAG regulators may control secretory traffic. By transforming DAG into phosphatidic acid (PA), diacylglycerol kinase α (DGKα) is essential for the negative control of DAG function in T lymphocytes. 22 DGKα translocates transiently to the T-cell membrane after human muscarinic type 1 receptor (HM1R) triggering or to the immune synapse (IS) after TCR stimulation; at these subcellular locations, DGKα acts as a negative modulator of phospholipase C (PLC)-generated DAG. 23,24 The secretory vesicle pathway involves several DAGc...

show abstract

Section: Discussionmentioning

confidence: 99%

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

et al. 2015

View full text Add to dashboard Cite

show abstract

“…RCPdependent a5b1 trafficking promotes invasive migration in three-dimensional matrices, which is characterised by the extension of invasive pseudopods. The production of phosphatidic acid within the pseudopod tip is required to localise RCP and permit integrin recycling (Rainero et al, 2012). Rather than influence a5b1 activity, a5b1 and RCP recruit EGF receptor 1 (EGFR1) and coordinate its recycling, which, in turn, potentiates EGFR activation and downstream signalling to promote invasion Muller et al, 2009).…”

Section: Integrin Trafficking Promotes Tumour Cell Invasion and Metasmentioning

confidence: 99%

Integrin trafficking at a glance

Bridgewater

Norman

Caswell

2012

Journal of Cell Science

Self Cite

169

167

View full text Add to dashboard Cite

“…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). Further studies are needed to determine whether Rab13 regulates the delivery of integrincontaining vesicles by interacting with Rab-coupling protein.…”

Section: Cell Migration and Scatteringmentioning

confidence: 99%

Regulation of Cancer Cell Behavior by the Small GTPase Rab13

Ioannou

McPherson

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration

Abstract: Phosphatidic acid generation by DGK-α is essential for the localization of Rab11-coupling protein to invasive pseudopods and subsequent invasive migration by tumor cells.

Cited by 114 publications

References 44 publications

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes

Integrin trafficking at a glance

Regulation of Cancer Cell Behavior by the Small GTPase Rab13

Contact Info

Product

Resources

About