Functional Mapping of the Cytoplasmic Region of Intercellular Adhesion Molecule-3 Reveals Important Roles for Serine Residues

Hayflick, Joel S.; Stine, Johnny T.; Fox, Roy; Hoekstra, Denise; Gallatin, W. Michael

doi:10.1074/jbc.272.35.22207

Cited by 12 publications

(17 citation statements)

References 38 publications

(31 reference statements)

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“…The ICAM-1 promoter contains potential binding sites for a variety of transcriptional regulatory factors, including the CRE motif that can bind to p300/CBP complex (19,70). Interestingly, the active promoter sequence of both ICAM-1 and -2 are homologous but differ in comparison to that of the ICAM-3 promoter (32), and this may explain the selective down-modulation ICAM-1 and -2 by p12 I . Adhesion through LFA-1 and ICAM is required for effective NK cell synapse formation and polarization, but cooperative signaling through engagement of NK cell activating receptors (NCR and NKG2D) with their ligands on target cells is necessary for degranulation and effective destruction of the target cells by NK cells (49,50).…”

Section: Discussionmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 (HTLV-1) p12^IDown-Modulates ICAM-1 and -2 and Reduces Adherence of Natural Killer Cells, Thereby Protecting HTLV-1-Infected Primary CD4⁺T Cells from Autologous Natural Killer Cell-Mediated Cytotoxicity despite the Reduction of Major Histocompatibility Complex Class I Molecules on Infected Cells

Banerjee

Feuer

Barker

2007

J Virol

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Section: Discussionmentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 (HTLV-1) p12^IDown-Modulates ICAM-1 and -2 and Reduces Adherence of Natural Killer Cells, Thereby Protecting HTLV-1-Infected Primary CD4⁺T Cells from Autologous Natural Killer Cell-Mediated Cytotoxicity despite the Reduction of Major Histocompatibility Complex Class I Molecules on Infected Cells

Banerjee

Feuer

Barker

2007

J Virol

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“…35 In addition, two other unrelated membrane proteins, CD44 and ICAM-3, which are also ezrin-binding partners, were shown to be phosphorylated by PKC at similar serine residues in their juxtamembrane regions. 36,37 Phosphorylation of the juxtamembrane serine residue of CD44 was shown to modulate direct interaction with ezrin and to be critical for CD44-dependent directional cell motility. 37 All these proteins have in common not only that they have a juxtamembrane PKC phosphorylation site, but also they are all heavily sialylated, O-linked glycoproteins.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Podocalyxin (Ser415) Prevents RhoA and Ezrin Activation and Disrupts Its Interaction with the Actin Cytoskeleton

Fukasawa

Obayashi

Schmieder

et al. 2011

The American Journal of Pathology

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Podocalyxin (PC) is a polysialylated, anti-adhesin that is essential for maintaining foot process architecture and the integrity of the glomerular filtration barrier. We showed previously that PC is firmly attached to the actin cytoskeleton through ezrin, that in puromycin aminonucleoside (PAN)-mediated nephrosis the PC-ezrin-actin complex is disrupted, and that PC is uncoupled from actin. However, the precise mechanisms involved remained unknown. Here we show that detachment of PC from actin is regulated by phosphorylation of PC. PC is hyperphosphorylated at serines in PAN-and protamine sulfate (PS)-treated rat glomeruli. We determined that PC is a substrate of PKC and that the site of phosphorylation is Ser415, located within the juxtamembrane, ezrin-binding domain of the cytoplasmic tail of PC. Mutation of Ser415 to the phosphomimetic residues Glu (S415E) or Asp (S415D) interfered with direct binding of the PC cytoplasmic tail to ezrin in vitro. Moreover, stable expression of a phosphomimetic (S415E) PC mutant but not the WT or the phosphorylation-deficient (S415A) PC mutant, disrupted PC-ezrin-actin interaction, failed to activate RhoA, and the cytoskeletal linker, ezrin, remained inactive. Our data indicate that phosphorylation of PC at Ser415 prevents attachment of PC and ezrin to actin and highlights the strategic position of Ser415 and direct binding of PC to ezrin in regulating podocyte foot process architecture.

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“…Another possibility is that serine residues near these regions play a role to provide a particular conformation for ERM binding; this binding could be regulated by phosphorylation. In this regard, it has been described the PKC-mediated phosphorylation of serine residues in the ICAM-3 cytoplasmic tail (28,42). Phosphorylation of intracellular Ser 489 of ICAM-3 plays a key role for IL-2 secretion, aggregation, and spreading of Jurkat cells co-stimulated with anti-ICAM-3 mAb (28), and substitution of Ser 487 and Ser 496 by Ala significantly decreased IL-2 secretion and cell spreading, respectively, induced by anti-ICAM-3 mAb (28).…”

Section: Figmentioning

confidence: 99%

“…In this regard, it has been described the PKC-mediated phosphorylation of serine residues in the ICAM-3 cytoplasmic tail (28,42). Phosphorylation of intracellular Ser 489 of ICAM-3 plays a key role for IL-2 secretion, aggregation, and spreading of Jurkat cells co-stimulated with anti-ICAM-3 mAb (28), and substitution of Ser 487 and Ser 496 by Ala significantly decreased IL-2 secretion and cell spreading, respectively, induced by anti-ICAM-3 mAb (28). In addition, PMA-induced phosphorylation of ICAM-3 redistributes it uniformly on the plasma membrane of lymphocytes (29).…”

Section: Figmentioning

confidence: 99%

“…There are two serine residues (Ser 487 and Ser 489 ) adjacent and one (Ser 496 ) within the amino acid segment lost from Y498stop to Y490stop mutant, which have been shown to be involved in ICAM-3-mediated activation and spreading of T cells (28). A detailed mutational analysis of this region (residues 487-503) showed that binding of N-moesin and N-ezrin to S487A, S489A, S496A, and T497A point mutations was reduced, whereas R493A and S503A mutants bound both ERM proteins at levels comparable with those of the wild type protein (Fig.…”

Section: Serine Residues In the Cytoplasmic Tail Of Icam-3 Are Criticmentioning

confidence: 99%

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A Novel Serine-rich Motif in the Intercellular Adhesion Molecule 3 Is Critical for Its Ezrin/Radixin/Moesin-directed Subcellular Targeting

Serrador¹,

Vicente‐Manzanares²,

Calvo³

et al. 2002

Journal of Biological Chemistry

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The relationship between adhesion receptors and the cytoskeleton is crucial for leukocyte migration and cell-cell interactions (1). In migrating leukocytes, ICAMs 1 are redistributed to the cellular uropod, a membrane protrusion at the rear of the cells (2). ICAMs act as both adhesion and signaling receptors and have partially overlapping functions (3). The ␤ 2 integrin LFA-1 specifically binds to the intercellular adhesion molecules ICAM-1, -2, and -3 (4 -6). ICAM-3 is highly expressed in naive T cells and interacts preferentially with two additional ligands, the integrin ␣ D ␤ 2 (7) and DC-SIGN, a novel C-type lectin expressed in dendritic cells that binds with high affinity to ICAM-3 (8). ICAM-3-DC-SIGN interaction seems to play a key role during the initiation of the immune response. ICAMs are co-localized with members of the ezrin, moesin, and radixin family of proteins in several cell types (9, 10). The latter proteins are thought to connect constituents of the plasma membrane with the cytoskeleton and are commonly associated with protrusive formations such as microvilli, microspikes, and filopodia (11,12). In leukocytes, ERM proteins are concentrated at the tips of microvilli (13,14), facilitating macrophage phagocytosis (15) and CD95-mediated apoptosis of T cells (16). Interactions between ICAM-1, ICAM-2, and moesin/ezrin/radixin have been studied previously in vitro (10, 17). The functional relevance of such interactions has been illustrated for natural killer cellmediated killing of target cells (18) and for microvillar organization during cortical morphogenesis (19).We have investigated here the dynamics of the interaction of ERM proteins with ICAM-3 and the critical residues in its cytoplasmic region, accounting both for binding to moesin and ezrin and for targeting of this adhesion receptor to the cellular uropod. EXPERIMENTAL PROCEDURESAntibodies, Cells, and Reagents-The anti-ICAM-3 HP2/19, TP1/24 and TP1/25; anti-CD4 HP2/6; anti-ICAM-1 RR1.1; anti-LFA-1␣ TS1/11; anti-CD45 D3/9; and anti-moesin/radixin 38/87 mAb have been described (2, 9, 20). The blocking anti-ICAM-3 140.11 mAb was generously provided by Dr. R. Vilella (Hospital Clinic, Barcelona, Spain). The anti-LFA-1␣ NKI-L16 mAb was generously provided by Dr. C. G. Figdor (University Hospital, Nijmegen, The Netherlands). The anti-ICAM-3 polyclonal antiserum (pAb) was generously provided by Dr. D. Simmons (Imperial Cancer Research Fund Laboratories, Oxford, United Kingdom). The anti-moesin 95/2 and the anti-ezrin 90/3 pAbs were raised in rabbits by immunization with recombinant human moesin and purified human ezrin, respectively, and the former was purified by affinity chromatography (13). The affinity-purified polyclonal antibody 454 raised against a unique peptide from mouse moesin was generously provided by Dr.

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Functional Mapping of the Cytoplasmic Region of Intercellular Adhesion Molecule-3 Reveals Important Roles for Serine Residues

Cited by 12 publications

References 38 publications

Phosphorylation of Podocalyxin (Ser415) Prevents RhoA and Ezrin Activation and Disrupts Its Interaction with the Actin Cytoskeleton

A Novel Serine-rich Motif in the Intercellular Adhesion Molecule 3 Is Critical for Its Ezrin/Radixin/Moesin-directed Subcellular Targeting

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