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1.
bioRxiv ; 2023 Jul 21.
Article in English | MEDLINE | ID: mdl-37503122

ABSTRACT

Collective cell migration occurs in various biological processes such as development, wound healing and metastasis. During Drosophila oogenesis, border cells (BC) form a cluster that migrates collectively inside the egg chamber. The Ste20-like kinase Misshapen (Msn) is a key regulator of BC migration coordinating the restriction of protrusion formation and contractile forces within the cluster. Here, we demonstrate that the kinase Tao acts as an upstream activator of Msn in BCs. Depletion of Tao significantly impedes BC migration and produces a phenotype similar to Msn loss-of-function. Furthermore, we show that the localization of Msn relies on its CNH domain, which interacts with the small GTPase Rap2l. Our findings indicate that Rap2l promotes the trafficking of Msn to the endolysosomal pathway. When Rap2l is depleted, the levels of Msn increase in the cytoplasm and at cell-cell junctions between BCs. Overall, our data suggest that Rap2l ensures that the levels of Msn are higher at the periphery of the cluster through the targeting of Msn to the degradative pathway. Together, we identified two distinct regulatory mechanisms that ensure the appropriate distribution and activation of Msn in BCs.

2.
Life Sci Alliance ; 6(9)2023 09.
Article in English | MEDLINE | ID: mdl-37369604

ABSTRACT

Collective cell migration is not only important for development and tissue homeostasis but can also promote cancer metastasis. To migrate collectively, cells need to coordinate cellular extensions and retractions, adhesion sites dynamics, and forces generation and transmission. Nevertheless, the regulatory mechanisms coordinating these processes remain elusive. Using A431 carcinoma cells, we identify the kinase MAP4K4 as a central regulator of collective migration. We show that MAP4K4 inactivation blocks the migration of clusters, whereas its overexpression decreases cluster cohesion. MAP4K4 regulates protrusion and retraction dynamics, remodels the actomyosin cytoskeleton, and controls the stability of both cell-cell and cell-substrate adhesion. MAP4K4 promotes focal adhesion disassembly through the phosphorylation of the actin and plasma membrane crosslinker moesin but disassembles adherens junctions through a moesin-independent mechanism. By analyzing traction and intercellular forces, we found that MAP4K4 loss of function leads to a tensional disequilibrium throughout the cell cluster, increasing the traction forces and the tension loading at the cell-cell adhesions. Together, our results indicate that MAP4K4 activity is a key regulator of biomechanical forces at adhesion sites, promoting collective migration.


Subject(s)
Cell-Matrix Junctions , Cytoskeleton , Cell Adhesion/physiology , Cell Movement/physiology , Phosphorylation
3.
Nat Commun ; 10(1): 3940, 2019 09 02.
Article in English | MEDLINE | ID: mdl-31477736

ABSTRACT

Collective cell migration is involved in development, wound healing and metastasis. In the Drosophila ovary, border cells (BC) form a small cluster that migrates collectively through the egg chamber. To achieve directed motility, the BC cluster coordinates the formation of protrusions in its leader cell and contractility at the rear. Restricting protrusions to leader cells requires the actin and plasma membrane linker Moesin. Herein, we show that the Ste20-like kinase Misshapen phosphorylates Moesin in vitro and in BC. Depletion of Misshapen disrupts protrusion restriction, thereby allowing other cells within the cluster to protrude. In addition, we show that Misshapen is critical to generate contractile forces both at the rear of the cluster and at the base of protrusions. Together, our results indicate that Misshapen is a key regulator of BC migration as it coordinates two independent pathways that restrict protrusion formation to the leader cells and induces contractile forces.


Subject(s)
Actomyosin/genetics , Cell Movement/genetics , Drosophila Proteins/genetics , Drosophila melanogaster/genetics , Gene Expression Regulation, Developmental , Oogenesis/genetics , Protein Serine-Threonine Kinases/genetics , Actin Cytoskeleton/metabolism , Actomyosin/metabolism , Algorithms , Animals , Animals, Genetically Modified , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Female , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Models, Genetic , Protein Serine-Threonine Kinases/metabolism , RNA Interference
4.
FASEB J ; 28(4): 1910-23, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24371122

ABSTRACT

The scavenger receptor CD36 plays a central role in lipid metabolism by promoting macrophage cholesterol efflux with the potential to reduce atherosclerotic lesions. However, the effect of CD36 on de novo cholesterol synthesis is not known. Here, we describe the cellular mechanism by which CD36 activation induces cholesterol depletion in HepG2 cells. Using the CD36 ligand hexarelin, we found a rapid phosphorylation of HMG-CoA reductase Ser-872 in treated cells, resulting in inactivation of the rate-limiting enzyme in sterol synthesis. Degradation of HMG-CoA reductase by the ubiquitin-proteasome pathway was also enhanced by hexarelin, through an increased recruitment of the anchor proteins insulin-induced gene (Insig)-1 and Insig-2. Genes encoding key enzymes involved in cholesterol synthesis and under the control of transcription factor sterol regulatory element-binding protein (SREBP)-2 remained unresponsive to sterol depletion, due to retention of the SREBP-2 escort protein Scap by Insig-1/2. Insig1 and Insig2 gene expression was also increased through activation of nuclear receptor peroxisome-proliferator activating receptor γ (PPARγ) by CD36, which lifted the inhibitory effect of PPARγ1 Ser-84 phosphorylation. Recruitment of coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) to activated AMPKα was also promoted, resulting in PGC-1α transcriptional activation through Sirt1-mediated deacetylation, increased recruitment of PPARγ, and up-regulation of Insig-1/2, revealing a regulatory role of CD36 on PGC-1α signaling. Our data identify CD36 as a novel regulator of HMG-CoA reductase function and Insig-1/2 expression, 2 critical steps regulating cholesterol synthesis in hepatocytes.


Subject(s)
CD36 Antigens/metabolism , Cholesterol/biosynthesis , Hepatocytes/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , PPAR gamma/metabolism , Transcription Factors/metabolism , AMP-Activated Protein Kinases/metabolism , Blotting, Western , CD36 Antigens/genetics , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Hep G2 Cells , Hepatocytes/pathology , Humans , Hydroxymethylglutaryl CoA Reductases/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Oligopeptides/pharmacology , PPAR gamma/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Phosphorylation/drug effects , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Serine/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Sterol Regulatory Element Binding Protein 2/genetics , Sterol Regulatory Element Binding Protein 2/metabolism , Transcription Factors/genetics
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