Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA

Gavrieli, Maya; Murphy, Kenneth M.

doi:10.1016/j.bbrc.2006.05.036

Cited by 74 publications

(71 citation statements)

References 24 publications

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“…This suggests that in VSMCs Grb2 recruitment to SHPS-1 via Shc functions to localize p85 to this SHPS-1 complex. This is supported by a recent report that phosphotyrosyl peptides derived from B and T lymphocyte attenuator, which has strong sequence homology with SHPS-1, associated directly with Grb2 and recruited p85 through Grb2 association (46).…”

Section: Discussionsupporting

confidence: 64%

Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells

Radhakrishnan¹,

Maile²,

Ling³

et al. 2008

Journal of Biological Chemistry

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Insulin-like growth factor-I (IGF-I) stimulates vascular smooth muscle cell proliferation and migration by activating both MAPK and phosphatidylinositol 3-kinase (PI3K). Vascular smooth muscle cells (VSMCs) maintained in 25 mM glucose sustain MAPK activation via increased Shc phosphorylation and Grb2 association resulting in an enhanced mitogenic response compared with cells grown in 5 mM glucose. PI3K plays a major role in IGF-I-stimulated VSMC migration, and hyperglycemia augments this response. In contrast to MAPK activation the role of Shc in modulating PI3K in response to IGF-I has not been determined. In this study we show that impaired Shc association with Grb2 results in decreased Grb2-p85 association, SHPS-1-p85 recruitment, and PI3K activation in response to IGF-I. Exposure of VSMCs to cell-permeable peptides, which contained polyproline sequences from p85 proposed to mediate Grb2 association, resulted in inhibition of Grb2-p85 binding and AKT phosphorylation. Transfected cells that expressed p85 mutant that had specific prolines mutated to alanines resulted in less Grb2-p85 association, and a Grb2 mutant (W36A/ W193A) that attenuated p85 binding showed decreased association of p85 with SHPS-1, PI3K activation, AKT phosphorylation, cell proliferation, and migration in response to IGF-I. Cellular exposure to 25 mM glucose, which is required for Shc phosphorylation in response to IGF-I, resulted in enhanced Grb2 binding to p85, activation of PI3K activity, and increased AKT phosphorylation as compared with cells exposed to 5 mM glucose. We conclude that in VSMCs exposed to hyperglycemia, IGF-I stimulation of Shc facilitates the transfer of Grb2 to p85 resulting in enhanced PI3K activation and AKT phosphorylation leading to enhanced cell proliferation and migration. Insulin-like growth factor-I (IGF-I)2 stimulates proliferation and migration in vascular smooth muscle cells (VSMCs) (1). IGF-I-stimulated VSMC migration and/or proliferation requires ligand occupancy of the ␣V␤3 integrin (2). Activation of the IGF-I receptor is coupled to downstream signaling events via recruitment and phosphorylation of two major adaptor proteins, Shc or members of the insulin receptor substrate (IRS) family. In VSMCs IGF-I stimulation leads to recruitment of the signaling protein Shc to SHP substrate-1 (SHPS-1) allowing sustained MAPK activation (3). IGF-I stimulation of phosphatidylinositol 3-kinase (PI3K) is also required to induce VSMC migration (4). Hyperglycemia has been shown to increase the responsiveness of smooth muscle cells as well as other cell types to growth factor stimulation (5-9). Following IGF-I stimulation of porcine VSMCs maintained in hyperglycemic conditions (e.g. Ͼ12 mM glucose) there is an increase in Shc phosphorylation and subsequent Grb2 association resulting in sustained MAPK activation and enhanced cell proliferation. In contrast cells grown in 5 mM glucose do not show these changes (5). Mutation of three Shc tyrosine phosphorylation sites, Tyr-239/ 240/317, that are required for Grb2 associatio...

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Section: Discussionsupporting

confidence: 64%

Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells

Radhakrishnan¹,

Maile²,

Ling³

et al. 2008

Journal of Biological Chemistry

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“…Early in vitro experiments found that a synthesized 11-mer phospho-tyrosine peptide containing this domain with a phosphorylated tyrosine 226 residue from BTLA could recruit Grb-2-PI3K. 8 Grb-2 has also been found to be able to recruit PtdIns-3K via its interaction with c-Cbl after TCR crosslinking on Jurkat T cells. 47 These observations and concepts suggest that BTLA signaling may also lead to a scenario in cancer where, in the context of chronic antigen stimulation within the tumor microenvironment, BTLA ligation by melanoma tumors that express HVEM 6 may inhibit or arrest further cell division and differentiation of CD8 C TIL while enhancing their survival, leading to their accumulation in an incompletely differentiated state in tumors.…”

Section: Discussionmentioning

confidence: 99%

“…5 In the platelet-derived growth factor (PDGF) receptor, this YXN motif has been found to bind to the signaling adaptor protein Grb-2 following phosphorylation of the tyrosine, leading to recruitment of phosphatidylinositol 3' kinase (PI-3K) and activation of Akt through serine phophorylation. 8,9,36 This suggests that HVEM-BTLA signaling could in fact have a prosurvival effect on TIL. To directly test whether BTLA ligation results in initiation of a prosurvival signal via phosphorylated Akt (pAkt), TIL were sorted into CD8 C BTLA C and CD8 C BTLA ¡ subsets and stimulated in vitro with HVEM-Fc fusion protein and anti-CD3 antibody.…”

Section: Btla Ligation Induces Pakt and Maintains Bad In A Phosphorylmentioning

confidence: 99%

“…6,7 However, recent studies by other groups have found that BTLA may also promote cell survival by inducing a gene expression program similar to that induced by ICOS and CD28 costimulation. 8,9 Although BTLA has been characterized as a negative costimulatory molecule on T cells, a number of studies of human CD8 C T cells have shown that BTLA is constitutively expressed at a high level on na€ ıve CD8 C T cells and gradually downregulated during T-cell expansion and cytotoxic T lymphocyte (CTL) differentiation. 6,10,11 A recent study suggested a close relationship between the expression of multiple inhibitory receptors (e.g., PD-1, TIM3, and LAG3) and antigen specificity, anatomic localization, and differentiation of CD8 C T cells in humans.…”

Section: Introductionmentioning

confidence: 99%

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BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

Haymaker

Ritthipichai

et al. 2015

OncoImmunology

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“…However, unlike PD-1 and CTLA-4, which bind members of the B7 Ig superfamily receptors, the established ligand for BTLA is the TNFR family member herpesvirus entry mediator (HVEM) (TNFRSF14) (3)(4)(5). HVEM binding leads to tyrosine phosphorylation of the cytoplasmic tail of BTLA, which contains a proposed Grb2/Grb2-related adaptor protein (Grap) docking site and two ITIMs (5)(6)(7)(8)(9)(10)(11). Biochemical analysis has revealed that phosphorylation at multiple tyrosines within the cytoplasmic tail of BTLA is necessary and required for efficient recruitment of protein tyrosine phosphatases and BTLA-mediated attenuation of T cell effector response and cell proliferation (5,8,10,11).…”

mentioning

confidence: 99%

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

Vendel¹,

Calemine-Fenaux²,

Izrael-Tomasevic³

et al. 2009

The Journal of Immunology

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B and T lymphocyte attenuator (BTLA) functions as a negative regulator of T cell activation and proliferation. Although the role of BTLA in regulating T cell responses has been characterized, a thorough investigation into the precise molecular mechanisms involved in BTLA-mediated lymphocyte attenuation and, more specifically, its role in regulating B cell activation has not been presented. In this study, we have begun to elucidate the biochemical mechanisms by which BTLA functions to inhibit B cell activation. We describe the cell surface expression of BTLA on various human B cell subsets and confirm its ability to attenuate B cell proliferation upon associating with its known ligand, herpesvirus entry mediator (HVEM). BTLA associates with the BCR and, upon binding to HVEM, recruits the tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 and reduces activation of signaling molecules downstream of the BCR. This is exemplified by a quantifiable decrease in tyrosine phosphorylation of the protein tyrosine kinase Syk, as measured by absolute quantification mass spectrometry. T he B and T lymphocyte attenuator (BTLA) 2 is an Ig superfamily coinhibitory receptor with structural and functional similarities to programmed cell death 1 (PD-1) and CTLA-4 (1-3). However, unlike PD-1 and CTLA-4, which bind members of the B7 Ig superfamily receptors, the established ligand for BTLA is the TNFR family member herpesvirus entry mediator (HVEM) (TNFRSF14) (3-5). HVEM binding leads to tyrosine phosphorylation of the cytoplasmic tail of BTLA, which contains a proposed Grb2/Grb2-related adaptor protein (Grap) docking site and two ITIMs (5-11). Biochemical analysis has revealed that phosphorylation at multiple tyrosines within the cytoplasmic tail of BTLA is necessary and required for efficient recruitment of protein tyrosine phosphatases and BTLA-mediated attenuation of T cell effector response and cell proliferation (5,8,10,11).The role of BTLA appears to be limited to lymphocyte activation as shown in BTLA-deficient mice, which present normal lymphoid organ development and near wild-type lymphocyte numbers. However, these mice display hyperproliferative T and B cell responses to TCR-and BCR-mediated activation, respectively (9, 11). Furthermore, loss of BTLA function leads to increased susceptibility to experimental autoimmune encephalomyelitis and MHC-mismatched allograft rejection, supporting the role of BTLA in modulating T cell activation and effector responses (11,12).Surface expression analysis of BTLA indicates that it is expressed on a wide number of lymphocytes in mice. It is most highly expressed on B cells, followed by CD4 ϩ T cells, and lower expression on CD8 ϩ T cells, macrophages, dendritic cells, and NK cells (9, 13). During murine B cell development, BTLA expression first appears in pre-B cells and shows increased expression through B cell maturation, with the highest expression on mature B cells (9). In this study, we show a detailed cell surface expression profile of BTLA during human B cell deve...

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Association of Grb-2 and PI3K p85 with phosphotyrosile peptides derived from BTLA

Cited by 74 publications

References 24 publications

Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells

Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

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