CIP4 Controls CCL19-Driven Cell Steering and Chemotaxis in Chronic Lymphocytic Leukemia

Malet-Engra, Gema; Viaud, Julien; Ysebaert, Loïc; Farcé, Manon; Lafouresse, Fanny; Laurent, Guy; Gaits‐Iacovoni, Frédérique; Scita, Giorgio; Dupré, Loı̈c

doi:10.1158/0008-5472.can-12-3564

Cited by 19 publications

(21 citation statements)

References 59 publications

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“…To test this possibility, the chronic lymphocytic leukemia (CLL)-derived cell line JVM3 was chosen as an experimental model [6]. As a result of homotypic cell-cell adhesion, JVM3 cells assembled into circular multicellular clusters, the size of which increased upon CCL19 stimulation (Figure S1A available online).…”

Section: Resultsmentioning

confidence: 99%

Collective Cell Motility Promotes Chemotactic Prowess and Resistance to Chemorepulsion

et al. 2015

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Collective cell migration is a widespread biological phenomenon, whereby groups of highly coordinated, adherent cells move in a polarized fashion. This migration mode is a hallmark of tissue morphogenesis during development and repair and of solid tumor dissemination. In addition to circulating as solitary cells, lymphoid malignancies can assemble into tissues as multicellular aggregates. Whether malignant lymphocytes are capable of coordinating their motility in the context of chemokine gradients is, however, unknown. Here, we show that, upon exposure to CCL19 or CXCL12 gradients, malignant B and T lymphocytes assemble into clusters that migrate directionally and display a wider chemotactic sensitivity than individual cells. Physical modeling recapitulates cluster motility statistics and shows that intracluster cell cohesion results in noise reduction and enhanced directionality. Quantitative image analysis reveals that cluster migration runs are periodically interrupted by transitory rotation and random phases that favor leader cell turnover. Additionally, internalization of CCR7 in leader cells is accompanied by protrusion retraction, loss of polarity, and the ensuing replacement by new leader cells. These mechanisms ensure sustained forward migration and resistance to chemorepulsion, a behavior of individual cells exposed to steep CCL19 gradients that depends on CCR7 endocytosis. Thus, coordinated cluster dynamics confer distinct chemotactic properties, highlighting unexpected features of lymphoid cell migration.

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Section: Resultsmentioning

confidence: 99%

Collective Cell Motility Promotes Chemotactic Prowess and Resistance to Chemorepulsion

et al. 2015

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“…Furthermore, the localization of the BAR protein is also expected to affect its ability to form higher order structures, and, importantly, proteins with similar structures do not necessarily localize in the same areas of the cellular membrane. For example, the F-BAR protein FBP17 is reported to localize at clathrin-coated pits (260), while its homolog, CIP4, can localize to lamellipodia (163,236,297). In addition, although the three PACSIN isoforms have a similar structure, PACSIN2 and -3 were localized at caveolae, while PACSIN1 was not (254).…”

Section: G Higher Order Structure Assemblymentioning

confidence: 99%

Dynamic Shaping of Cellular Membranes by Phospholipids and Membrane-Deforming Proteins

Suetsugu

Kurisu

Takenawa

2014

Physiological Reviews

204

207

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All cellular compartments are separated from the external environment by a membrane, which consists of a lipid bilayer. Subcellular structures, including clathrin-coated pits, caveolae, filopodia, lamellipodia, podosomes, and other intracellular membrane systems, are molded into their specific submicron-scale shapes through various mechanisms. Cells construct their micro-structures on plasma membrane and execute vital functions for life, such as cell migration, cell division, endocytosis, exocytosis, and cytoskeletal regulation. The plasma membrane, rich in anionic phospholipids, utilizes the electrostatic nature of the lipids, specifically the phosphoinositides, to form interactions with cytosolic proteins. These cytosolic proteins have three modes of interaction: 1) electrostatic interaction through unstructured polycationic regions, 2) through structured phosphoinositide-specific binding domains, and 3) through structured domains that bind the membrane without specificity for particular phospholipid. Among the structured domains, there are several that have membrane-deforming activity, which is essential for the formation of concave or convex membrane curvature. These domains include the amphipathic helix, which deforms the membrane by hemi-insertion of the helix with both hydrophobic and electrostatic interactions, and/or the BAR domain superfamily, known to use their positively charged, curved structural surface to deform membranes. Below the membrane, actin filaments support the micro-structures through interactions with several BAR proteins as well as other scaffold proteins, resulting in outward and inward membrane micro-structure formation. Here, we describe the characteristics of phospholipids, and the mechanisms utilized by phosphoinositides to regulate cellular events. We then summarize the precise mechanisms underlying the construction of membrane micro-structures and their involvements in physiological and pathological processes.

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“…CIP4 is overexpressed in normal epithelial cells undergoing the epithelial-mesenchymal transition (Zhang et al, 2013). CIP4 is also overexpressed in osteosarcoma (Koshkina et al, 2013), in chronic lymphocytic leukemia (Malet-Engra et al, 2013), in non-small cell lung cancer (Truesdell et al, 2014) and in a subset of invasive breast cancer cells (Pichot et al, 2010). In every case, interfering with CIP4 function leads to defective cell migration.…”

Section: Discussionmentioning

confidence: 99%

Centrosomal AKAP350 and CIP4 act in concert to define centrosome/Golgi polarity in migratory cells

Tonucci

Hidalgo

Ferretti

et al. 2015

Journal of Cell Science

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The acquisition of a migratory phenotype is central in processes as diverse as embryo differentiation and tumor metastasis. An early event in this phenomenon is the generation of a nucleuscentrosome-Golgi back-to-front axis. AKAP350 (also known as AKAP9) is a Golgi and centrosome scaffold protein that is involved in microtubule nucleation. AKAP350 interacts with CIP4 (also known as TRIP10), a cdc42 effector that regulates actin dynamics. The present study aimed to characterize the participation of centrosomal AKAP350 in the acquisition of migratory polarity, and the involvement of CIP4 in the pathway. The decrease in total or in centrosomal AKAP350 led to decreased formation of the nucleus-centrosomeGolgi axis and defective cell migration. CIP4 localized at the centrosome, which was enhanced in migratory cells, but inhibited in cells with decreased centrosomal AKAP350. A decrease in the CIP4 expression or inhibition of the CIP4-AKAP350 interaction also led to defective cell polarization. Centrosome positioning, but not nuclear movement, was affected by loss of CIP4 or AKAP350 function. Our results support a model in which AKAP350 recruits CIP4 to the centrosome, providing a centrosomal scaffold to integrate microtubule and actin dynamics, thus enabling centrosome polarization and ensuring cell migration directionality.

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CIP4 Controls CCL19-Driven Cell Steering and Chemotaxis in Chronic Lymphocytic Leukemia

Cited by 19 publications

References 59 publications

Collective Cell Motility Promotes Chemotactic Prowess and Resistance to Chemorepulsion

Collective Cell Motility Promotes Chemotactic Prowess and Resistance to Chemorepulsion

Dynamic Shaping of Cellular Membranes by Phospholipids and Membrane-Deforming Proteins

Centrosomal AKAP350 and CIP4 act in concert to define centrosome/Golgi polarity in migratory cells

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