Phosphorylated Pleckstrin Induces Cell Spreading via an Integrin-Dependent Pathway

Roll, Richard; Bauman, Eve Marie; Bennett, Joel S.; Abrams, Charles S.

doi:10.1083/jcb.150.6.1461

Cited by 20 publications

(20 citation statements)

References 26 publications

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“…PLEK (pleckstrin) plays an important role in proinflammatory cytokine activation (tumor necrosis factor α and IL1B) [46]. Its overexpression alters cytoskeletal organization and cell spreading [47]. It is less methylated and more expressed in MSE Endo versus ESE Endo and PE Endo , and also less methylated and more expressed in MSE Endo than MSE Control .…”

Section: Discussionmentioning

confidence: 99%

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Houshdaran

Nezhat

et al. 2016

Biology of Reproduction

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Endometriosis is an estrogen-dependent, progesterone-resistant disorder largely derived from retrograde transplantation of menstrual tissue/cells into the pelvis, eliciting an inflammatory response, pelvic pain, and infertility. Eutopic endometrium (within the uterus), giving rise to pelvic disease, displays cycle-dependent transcriptomic, proteomic, and signaling abnormalities, and although its DNA methylation profiles dynamically change across the cycle in healthy women, studies in endometriosis are limited. Herein, we investigated the DNA methylome and associated gene expression in three phases of the cycle in eutopic endometrium of women with severe endometriosis versus controls, matched for ethnicity, medications, smoking, and no recent contraceptive steroid use. Genome-wide DNA methylation and gene expression were coassessed in each sample. Cycle phase was determined by histology, serum hormone levels, and unsupervised principal component and hierarchical cluster analyses of microarray data. Altered endometrial DNA methylation in endometriosis was most prominent in the midsecretory phase (peak progesterone), with disruption of the normal pattern of cycle-dependent DNA methylation changes, including a bias toward methylation of CpG islands, suggesting wide-range abnormalities of the chromatin remodeling machinery in endometriosis. DNA methylation changes were associated with altered gene expression relevant to endometrial function/dysfunction, including cell proliferation, inflammation/immune response, angiogenesis, and steroid hormone response. The data provide insight into epigenetic reprogramming and steroid hormone actions in endometrium contributing to the pathogenesis and pathophysiology of endometriosis.

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Section: Discussionmentioning

confidence: 99%

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Houshdaran

Nezhat

et al. 2016

Biology of Reproduction

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“…[33][34][35] Heterologous expression studies show that pleckstrin can reorganize the actin cytoskeleton. 27,28,36 Because the available evidence suggests that disassembly of F-actin facilitates exocytosis in platelets, it is possible that pleckstrin indirectly links PKC with exocytosis by facilitating F-actin reorganization. Therefore, we analyzed the ability of pleckstrinnull platelets to increase their levels of F-actin in response to PMA.…”

Section: Pleckstrin and Actin Assemblymentioning

confidence: 99%

“…[23][24][25][26] Overexpression and microinjection studies suggest that pleckstrin is membrane localized, induces a shift of F-actin toward the cell cortex, and participates in the production of lamellipodia. 27,28 Those studies of cultured cell lines further suggest that pleckstrin induces these cellular changes through a signaling pathway that involves phospholipids, integrins, and small GTP-binding proteins of the Rho family. 29 These responses are tightly regulated by PKC-mediated phosphorylation of 3 residues in pleckstrin (Ser113, Thr114, and Ser117), located immediately after the amino-terminal PH domain.…”

Section: Introductionmentioning

confidence: 99%

Loss of pleckstrin defines a novel pathway for PKC-mediated exocytosis

Lian

Wang

Flick

et al. 2009

Blood

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Pleckstrin, the platelet and leukocyte C kinase substrate, is a prominent substrate of PKC in platelets, monocytes, macrophages, lymphocytes, and granulocytes. Pleckstrin accounts for 1% of the total protein in these cells, but it is best known for containing the 2 prototypic Pleckstrin homology, or PH, domains. Overexpressed pleckstrin can affect polyphosphoinositide second messengerbased signaling events; however, its true in vivo role has been unknown. Here, we describe mice containing a null mutation within the pleckstrin gene. Platelets lacking pleckstrin exhibit a marked defect in exocytosis of ␦ and ␣ granules, ␣IIb␤3 activation, actin assembly, and aggregation after exposure to the PKC stimulant, PMA. Pleckstrin-null platelets aggregate normally in response to thrombin, but they fail to aggregate in response to thrombin in the presence of PI3K inhibitors, suggesting that a PI3K-dependent signaling pathway compensates for the

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“…Because expression of pleckstrin-1 enhances cell spreading within adherent cell lines, 26,27 we analyzed whether pleckstrin-2 affected Jurkat T-cell spreading by quantifying the footprint sizes of Jurkat T cells overexpressing wild-type pleckstrin-2 or pleckstrin-2 mutants. We found that when pleckstrin-2-expressing Jurkat cells were nonspecifically adhered to poly-L-lysine-coated plates, there were only small changes in the cell-footprint size ( Figure 2C).…”

Section: Expression Of Pleckstrin-2 In Jurkat Cells Increases Cell Spmentioning

confidence: 99%

“…25 Pleckstrin-1 induces cell spreading and reorganization of the actin cytoskeleton. 26,27 These pleckstrin-1-mediated effects are entirely regulated by its phosphorylation state. Because pleckstrin-2 does not appear to be a phosphoprotein, we reasoned that its interaction with its binding partners or intracellular localization regulates its activity.…”

Section: Introductionmentioning

confidence: 99%

PI3K regulates pleckstrin-2 in T-cell cytoskeletal reorganization

Bach

Kerr

Wang

et al. 2006

Blood

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Pleckstrin-2 is composed of 2 pleckstrin homology (PH) domains and a disheveled-Egl-10-pleckstrin (DEP) domain. A lipid-binding assay revealed that pleckstrin-2 binds with greatest affinity to D3 and D5 phosphoinositides. Pleckstrin-2 expressed in Jurkat T cells bound to the cellular membrane and enhanced actindependent spreading only after stimulation of the T-cell antigen receptor or the integrin ␣4␤1. A pleckstrin-2 variant containing point mutations in both PH domains failed to associate with the Jurkat membrane and had no effect on spreading under the same conditions. Although still membrane bound, a pleckstrin-2 variant containing point mutations in the DEP domain demonstrated a decreased ability to induce membrane ruffles and spread. Pleckstrin-2 also colocalized with actin at the immune synapse and integrin clusters via its PH domains. Although pleckstrin-2 can bind to purified D3 and D5 phosphoinositides, the intracellular membrane association of pleckstrin-2 and cell spreading are dependent on D3 phosphoinositides, because these effects were disrupted by pharmacologic inhibition of phosphatidylinositol 3-kinase (PI3K). Our results indicate that pleckstrin-2 uses its modular domains to bind to membraneassociated phosphatidylinositols generated by PI3K, whereby it coordinates with the actin cytoskeleton in lymphocyte spreading and immune synapse formation. IntroductionPleckstrin-1, the platelet and leukocyte C kinase substrate, is the major substrate of protein kinase C (PKC) in platelets, monocytes, macrophages, lymphocytes, and granulocytes. 1 Its 350 amino acid sequence can be divided into 3 motifs: PH domains at the aminoand carboxy-termini of the molecule and an intervening DEP domain. 2-4 A short stretch of amino acids between the aminoterminal PH domain and the DEP domain contains 3 sites of phosphorylation (Ser113, Thr114, and Ser117) by PKC, which are essential for the function of pleckstrin-1. [5][6][7] PH domains have been identified in approximately 252 other human proteins (Simple Modular Architecture Research Tool [SMART] database) and are found in many molecules involved in cellular signaling, cytoskeletal organization, membrane trafficking, and phospholipid modification. 8 Previous results have suggested that PH domains mediate binding of their host proteins to certain phosphoinositides. [9][10][11] Consistent with this hypothesis, nearly all PH domain-containing proteins require membrane association for their function in signal transduction, including pathways that contribute to cytoskeletal assembly, membrane budding, and fusion. 4,7,[12][13][14][15] DEP homology domains are present in numerous signaling proteins, 3,16 including 67 found in the human genome (SMART database). The DEP domain is a protein module of approximately 100 amino acids, first found in the signaling proteins disheveled, Egl-10, and pleckstrin. 3 The domain is also present in certain kinases, regulators of G-protein signaling proteins (RGSs), and Epac, the cyclic adenosine monophosphateregulated guanine nucleotide ...

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Phosphorylated Pleckstrin Induces Cell Spreading via an Integrin-Dependent Pathway

Cited by 20 publications

References 26 publications

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

Loss of pleckstrin defines a novel pathway for PKC-mediated exocytosis

PI3K regulates pleckstrin-2 in T-cell cytoskeletal reorganization

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