LAT Palmitoylation

Zhang, Weiguo; Trible, Ronald P.; Samelson, Lawrence E.

doi:10.1016/s1074-7613(00)80606-8

Cited by 779 publications

(330 citation statements)

References 36 publications

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“…Conversely, a large portion of LAT was found in lipid rafts (Fig. 3B, fraction 3) as reported previously (27). A similar result was obtained when Daudi B cells were used (not shown).…”

Section: Resultssupporting

confidence: 90%

“…Interestingly, there is a cysteine residue near the C-terminal end of the transmembrane domain. Similar cysteine residues in LAT are palmitoylated and required for LAT localization to lipid rafts and tyrosine phosphorylation (27). The cytoplasmic domain of LAX protein contains many acidic residues (28 Glu and 26 Asp in human LAX) like LAT.…”

Section: Resultsmentioning

confidence: 99%

“…Separation of the cytosolic fraction and membrane fraction was performed using Dounce homogenization and ultracentrifugation. Purification of lipid rafts was done using a sucrose gradient (27).…”

Section: Methodsmentioning

confidence: 99%

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Molecular Cloning of a Novel Gene Encoding a Membrane-associated Adaptor Protein (LAX) in Lymphocyte Signaling

Zhu

Janssen

Leung

et al. 2002

Journal of Biological Chemistry

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Membrane-associated adaptors play an important role in coupling antigen receptor engagement to downstream signaling events, such as Ras-MAPK activation, Ca 2؉ flux, and nuclear factor of activated T cells (NFAT) activation. Here we identified a novel membrane-associated adaptor protein, LAX. LAX is mainly expressed in B cells, T cells, and other lymphoid-specific cell types. It shares no overall sequence homology with LAT and is not localized to lipid rafts. However, like LAT, LAX has tyrosine motifs for binding Grb2, Gads, and the p85 subunit of phosphatidylinositol 3-kinase. Upon stimulation via the B or T cell receptors, LAX is rapidly phosphorylated by Src and Syk family tyrosine kinases and interacts with Grb2, Gads, and p85. Overexpression of LAX in Jurkat cells specifically inhibits T cell receptor-mediated p38 MAPK activation and NFAT/AP-1 transcriptional activation. Our data suggested that LAX functions to negatively regulate signaling in lymphocytes.

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“…Conversely, a large portion of LAT was found in lipid rafts (Fig. 3B, fraction 3) as reported previously (27). A similar result was obtained when Daudi B cells were used (not shown).…”

Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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Molecular Cloning of a Novel Gene Encoding a Membrane-associated Adaptor Protein (LAX) in Lymphocyte Signaling

Zhu

Janssen

Leung

et al. 2002

Journal of Biological Chemistry

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“…In addition, since myristylation and palmitylation of Src family kinases target these proteins to cell membrane glycolipid-enriched microdomains (Resh, 1994), it will also be important to determine whether the SIMA135/CDCP1 consensus palmitylation signal is capable of such targeting. If this is demonstrated, the SIMA135/CDCP1 consensus palmitylation signal may provide a mechanism for regulation of signal transduction at the cell surface as has been shown for the T-cell integral membrane protein LAK (Zhang et al, 1998).…”

Section: Discussionmentioning

confidence: 84%

Subtractive immunization using highly metastatic human tumor cells identifies SIMA135/CDCP1, a 135 kDa cell surface phosphorylated glycoprotein antigen

et al. 2003

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We have previously used a subtractive immunization (SI) approach to generate monoclonal antibodies (mAbs) against proteins preferentially expressed by the highly metastatic human epidermoid carcinoma cell line, M + HEp3. Here we report the immunopurification, identification and characterization of SIMA135/CDCP1 (subtractive immunization M + HEp3 associated 135 kDa protein/CUB domain containing protein 1) using one of these mAbs designated 41-2. Protein expression levels of SIMA135/CDCP1 correlated with the metastatic ability of variant HEp3 cell lines. Protein sequence analysis predicted a cell surface location and type I orientation of SIMA135/CDCP1, which was confirmed directly by immunocytochemistry. Analysis of deglycosylated cell lysates indicated that up to 40 kDa of the apparent molecular weight of SIMA135/CDCP1 is because of N-glycosylation. Western blot analysis using a antiphosphotyrosine antibody demonstrated that SIMA135/ CDCP1 from HEp3 cells is tyrosine phosphorylated. Selective inhibitor studies indicated that an Src kinase family member is involved in the tyrosine phosphorylation of the protein. In addition to high expression in M + HEp3 cells, the SIMA135/CDCP1 protein is expressed to varying levels in 13 other human tumor cell lines, manifesting only a weak correlation with the reported metastatic ability of these tumor cell lines. The protein is not detected in normal human fibroblasts and endothelial cells. Northern blot analysis indicated that SIMA135/ CDCP1 mRNA has a restricted expression pattern in normal human tissues with highest levels of expression in skeletal muscle and colon. Immunohistochemical analysis indicated apical and basal plasma membrane expression of SIMA135/CDCP1 in epithelial cells in normal colon. In colon tumor, SIMA135/CDCP1 expression appeared dysregulated showing extensive cell surface as well as cytoplasmic expression. Consistent with in vitro shedding experiments on HEp3 cells, SIMA135/CDCP1 was also detected within the lumen of normal and cancerous colon crypts, suggesting that protein shedding may occur in vivo. Thus, specific immunodetection followed by proteomic analysis allows for the identification and partial characterization of a heretofore uncharacterized human cell surface antigen.

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“…LAT is a 36 kDa transmembrane protein containing no previously known protein ± protein interacting domains such as SH2, SH3, PTB or PH, just to mention a few. The palmitoylation of LAT targets it to cholesterol-rich lipid rafts and is required for its function in TCR signaling (Zhang et al, 1998b;Lin et al, 1999). LAT is tyrosine phosphorylated following TCR activation and the phosphotyrosine residues recruit the SH2 domains of Grb2 and PLCg1 (Zhang et al, 1998a).…”

Section: Nck Links Cell Surface Receptors To the Actin Cytoskeletonmentioning

confidence: 99%

Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton

2001

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In response to extracellular signals, cell surface receptors engage in connections with multiple intracellular signaling pathways, leading to the cellular responses such as survival, migration, proliferation and di erentiation. Thè pY?SH2/SH3?e ector' connection is a frequently used scheme by many cell surface receptors, in which SH2/SH3-containing adapters connect protein tyrosine phosphorylation to a variety of downstream e ector pathways. Following the initial landmark ®nding that Grb2 adapter links the receptors to the Ras pathway leading to DNA synthesis, recent studies have revealed that the biological function of the SH2/SH3 adapter Nck/Dock is to link cell surface receptors to the actin cytoskeleton. For example, in the evolutionarily-conserved signaling network, GEF-Rac-Nck-Pak, Nck`®xes up' the interaction of Pak with its upstream activator, Rac. The activated Pak then regulates the cytoskeletal dynamics. The fact that the majority of the more than 20 Nck-SH3-associated e ectors are regulators of the actin cytoskeleton suggests that Nck/Dock regulates, via binding to distinct e ectors, various cell type-speci®c motogenic responses. This review focuses on our current understanding of Nck/Dock function. Due to the number and complexity of the terminologies used in this review, à Glossary of Terms' is provided to help reduce confusions. Oncogene (2001) 20, 6403 ± 6417.Keywords: Src-homology domains; adapters; tyrosine kinases; signal transduction; cytoskeleton The SH2/SH3 adapters The src-homology 2 (SH2) and src-homlogy 3 (SH3) domains are protein ± protein interaction modules, found in a variety of structurally and functionally distinct signaling molecules, including protein tyrosine kinases/phosphatases, lipid kinase/phosphatase, guanine nucleotide exchange factors/GTPase activation proteins, docking proteins/adapters, cytoskeletal binding proteins and even transcription factors (Pawson, 1995;Mayer, 1999). Except for the terminology, SH2 and SH3 domains share no other common features regarding their structures, binding speci®city, and cellular targets. SH2 domains enable their host proteins to form complexes with phosphotyrosine (pY) proteins by binding to pY residues within these proteins. The stability and speci®city of the binding also depend upon the additional three to six amino acid residues immediately carboxyl to the pY residue, pY-(X) 3 ± 6 . Therefore, SH2 domains from di erent host molecules bind di erent pY-containing peptides. SH3 domains bind proline-rich segments of target molecules with a minimum consensus of P-x-x-P (Mayer, 2001). Each proline is often preceded by an aliphatic amino acid residue, and the aliphatic-proline pair binds to a hydrophobic pocket on SH3 domains. A major di erence between the SH2-pY binding and SH3-PxxP interactions is that the former is always transiently induced by extracellular signals, whereas the latter is often, but not always, constitutive. For instance, the SH2 domain of the adapter protein Grb2 only binds to tyrosine phosphorylated/activated EGFR, whe...

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LAT Palmitoylation

Cited by 779 publications

References 36 publications

Molecular Cloning of a Novel Gene Encoding a Membrane-associated Adaptor Protein (LAX) in Lymphocyte Signaling

Molecular Cloning of a Novel Gene Encoding a Membrane-associated Adaptor Protein (LAX) in Lymphocyte Signaling

Subtractive immunization using highly metastatic human tumor cells identifies SIMA135/CDCP1, a 135 kDa cell surface phosphorylated glycoprotein antigen

Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton

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