scholarly journals The ShcD phosphotyrosine adaptor protein exhibits novel binding characteristics with the TrkA neurotrophin receptor

SURG Journal ◽  
1969 ◽  
Vol 2 (1) ◽  
pp. 59-70
Author(s):  
Melanie Wills ◽  
Nina Jones
Keyword(s):  
Adaptor Protein ◽  
Neurotrophin Receptor ◽  
Binding Characteristics ◽  
Tyrosine Residues ◽  
Sh2 Domains ◽  
Downstream Signaling ◽  
Cytoplasmic Tails ◽  
Receptor Interactions ◽  
Src Homology ◽  
The Brain

Newly revealed ShcD has been characterized as an intracellular phosphotyrosine adaptor protein belonging to the Src homology and collagen (Shc) family. These scaffolding molecules facilitate receptor-mediated signal transduction through their ability to selectively recognize and bind, via PTB and SH2 domains, to phosphorylated tyrosine residues in the cytoplasmic tails of a variety of activated receptors. A central CH1 domain couples to downstream signaling molecules including Grb2. ShcD is most similar in form to ShcA; however, unlike the latter, its expression in the mouse is localized to the brain and skeletal muscle. Consistent with this observation, we report that human ShcD is able to bind the TrkA neurotrophin receptor responsive to nerve growth factor (NGF). This interaction is similar to that of other Shc proteins in that it is strongly influenced by the TrkA Tyr 490 residue, and results in ShcD phosphorylation. Surprisingly, we find that both the PTB and SH2 domains of ShcD impact its ability to complex with TrkA, in contrast to the PTB-mediated interaction documented for traditional Shc proteins. TrkA binding analyses performed with different ShcD mutants suggest that the contributions of the PTB and SH2 domains supercede simple co operativity, and are in fact reminiscent of auto-regulatory mechanisms. Here we report both the canonical and atypical characteristics of the ShcD / TrkA interaction, including novel proposed models of adaptor-receptor interactions.

scholarly journals APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl

Leukemia ◽  
1999 ◽  
Vol 13 (5) ◽  
pp. 760-767 ◽  
Author(s):  
T Wakioka ◽  
A Sasaki ◽  
K Mitsui ◽  
M Yokouchi ◽  
A Inoue ◽  
...  
Keyword(s):  
Adaptor Protein ◽  
Pleckstrin Homology ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology ◽  
Stat Pathway

scholarly journals Structural and functional elucidation of NF-κB signaling by the p75 neurotrophin receptor through recruitment of TRADD

2021 ◽  
Author(s):  
Ning Zhang ◽  
Lilian Kisiswa ◽  
Ajeena Ramanujan ◽  
Zhen Li ◽  
Eunice Weiling Sim ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Neurotrophin Receptor ◽  
Structural Basis ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
Structural Mechanism ◽  
Downstream Signaling ◽  
Developing Neurons

Abstractp75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. However, the structural mechanism and physiological relevance of the adaptor protein TRADD in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the complex between p75NTR-DD and TRADD-DD and elucidate the structural basis of specific DD recognition in the p75NTR/TRADD signaling pathway. Furthermore, we identify spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and reveal the functional role of TRADD recruitment to p75NTR in the regulation of canonical NF-κB signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75NTR through DD interactions creates a membrane-proximal platform to propagate downstream signaling in developing neurons.

scholarly journals LIME, a Novel Transmembrane Adaptor Protein, Associates with p56lck and Mediates T Cell Activation

2003 ◽  
Vol 198 (10) ◽  
pp. 1463-1473 ◽  
Author(s):  
Eun Mi Hur ◽  
Myoungsun Son ◽  
Ok-Hee Lee ◽  
Young Bong Choi ◽  
Changwon Park ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Transmembrane Domain ◽  
Adaptor Protein ◽  
Jurkat T Cells ◽  
Downstream Signaling ◽  
Src Homology

In this study, we identify and characterize a novel transmembrane adaptor protein, designated Lck-interacting membrane protein (LIME), as a binding partner of the Lck Src homology (SH)2 domain. LIME possesses a short extracellular domain, a transmembrane domain, and a cytoplasmic tail containing five tyrosine-based motifs. The protein is primarily expressed in hematopoietic cells and lung. Interestingly, LIME expression is up-regulated by TCR stimulation and sustained up to 24 h, suggesting that LIME acts throughout the early to late stages of T cell activation. LIME is localized to membrane rafts and distributed within the T cell–APC contact site. Upon TCR stimulation of Jurkat T cells, LIME associates with Lck as a tyrosine-phosphorylated protein. Experiments using Jurkat T cells expressing CD8–LIME chimera reveal that the protein associates with phosphatidylinositol 3-kinase, Grb2, Gads, and SHP2, and activates ERK1/2 and JNK but not p38. Moreover, overexpression of LIME in Jurkat T cells induces transcriptional activation of the IL-2 promoter. Our data collectively show that LIME is a raft-associated transmembrane adaptor protein linking TCR stimuli to downstream signaling pathways via associations with Lck.

scholarly journals Adaptor protein Lnk binds to and inhibits normal and leukemic FLT3

Blood ◽  
2012 ◽  
Vol 120 (16) ◽  
pp. 3310-3317 ◽  
Author(s):  
De-Chen Lin ◽  
Tong Yin ◽  
Maya Koren-Michowitz ◽  
Ling-Wen Ding ◽  
Saskia Gueller ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Adaptor Protein ◽  
Negative Regulator ◽  
Hematopoietic Progenitor Cell ◽  
Cytokine Signaling ◽  
Tyrosine Residues ◽  
Sh2 Domains ◽  
Multipotent Progenitors ◽  
Direct Binding ◽  
Tandem Duplications

Abstract Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase with important roles in hematopoietic progenitor cell survival and proliferation. It is mutated in approximately one-third of AML patients, mostly by internal tandem duplications (ITDs). Adaptor protein Lnk is a negative regulator of hematopoietic cytokine signaling. In the present study, we show that Lnk interacts physically with both wild-type FLT3 (FLT3-WT) and FLT3-ITD through the SH2 domains. We have identified the tyrosine residues 572, 591, and 919 of FLT3 as phosphorylation sites involved in direct binding to Lnk. Lnk itself was tyrosine phosphorylated by both FLT3 ligand (FL)–activated FLT3-WT and constitutively activated FLT3-ITD. Both shRNA-mediated depletion and forced overexpression of Lnk demonstrated that activation signals emanating from both forms of FLT3 are under negative regulation by Lnk. Moreover, Lnk inhibited 32D cell proliferation driven by different FLT3 variants. Analysis of primary BM cells from Lnk-knockout mice showed that Lnk suppresses the expansion of FL-stimulated hematopoietic progenitors, including lymphoid-primed multipotent progenitors. The results of the present study show that through direct binding to FLT3, Lnk suppresses FLT3-WT/ITD–dependent signaling pathways involved in the proliferation of hematopoietic cells. Therefore, modulation of Lnk expression levels may provide a unique therapeutic approach for FLT3-ITD–associated hematopoietic disease.

scholarly journals Behavioral analysis in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Tasuku Nishino ◽  
Kota Tamada ◽  
Akane Maeda ◽  
Takaya Abe ◽  
Hiroshi Kiyonari ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Neurotrophin Receptor ◽  
Receptor Signaling ◽  
Erk Mapk ◽  
Growth Factor Receptor Signaling ◽  
The Brain

Abstract Grb2-associated regulator of Erk/MAPK (GAREM), is an adaptor protein related to the several cell growth factor receptor-signaling. The GAREM family has two subtypes, GAREM1 and GAREM2, both encoded in the human and mouse genome. Recent genome-wide research identified GAREM2 as a candidate of neurodegenerative diseases. Here, we use knockout (KO) mice to show the role of GAREM2, that is highly expressed in the brain. According to the comprehensive behavioral battery, they exhibited less anxiety both in elevated plus maze and open field tests, mildly increased social approaching behavior in the reciprocal social interaction test, and longer latency to immobility in the tail suspension test as compared to wild-type (WT). Additionally, the extension of neurites in the primary cultured neurons was suppressed in ones derived from GAREM2 KO mice. Furthermore, we also identified Intersectin, as a binding partner of GAREM2 in this study. Intersectin is also a multi-domain adaptor protein that regulates endocytosis and cell signaling, which can potentially alter the subcellular localization of GAREM2. The important molecules, such as the neurotrophin receptor and Erk family, that are involved in the signaling pathway of the neural cell growth in the mouse brain, have been reported to participate in emotional behavior. As GAREM plays a role in the cellular growth factor receptor signaling pathway, GAREM2 may have a common role related to the transduction of Erk signaling in the higher brain functions.

scholarly journals An Adaptor Role for Cytoplasmic Sam68 in Modulating Src Activity during Cell Polarization

2009 ◽  
Vol 29 (7) ◽  
pp. 1933-1943 ◽  
Author(s):  
Marc-Étienne Huot ◽  
Claire M. Brown ◽  
Nathalie Lamarche-Vane ◽  
Stéphane Richard
Keyword(s):  
Plasma Membrane ◽  
Rho Gtpases ◽  
Cell Attachment ◽  
Adaptor Protein ◽  
Cell Polarization ◽  
Sh2 Domains ◽  
Src Homology 3 ◽  
Rac1 Activity ◽  
Small Rho Gtpases ◽  
Src Homology

ABSTRACT The Src-associated substrate during mitosis with a molecular mass of 68 kDa (Sam68) is predominantly nuclear and is known to associate with proteins containing the Src homology 3 (SH3) and SH2 domains. Although Sam68 is a Src substrate, little is known about the signaling pathway that link them. Src is known to be activated transiently after cell spreading, where it modulates the activity of small Rho GTPases. Herein we report that Sam68-deficient cells exhibit loss of cell polarity and cell migration. Interestingly, Sam68-deficient cells exhibited sustained Src activity after cell attachment, resulting in the constitutive tyrosine phosphorylation and activation of p190RhoGAP and its association with p120rasGAP. Consistently, we observed that Sam68-deficient cells exhibited deregulated RhoA and Rac1 activity. By using total internal reflection fluorescence microscopy, we observed Sam68 near the plasma membrane after cell attachment coinciding with phosphorylation of its C-terminal tyrosines and association with Csk. These findings show that Sam68 localizes near the plasma membrane during cell attachment and serves as an adaptor protein to modulate Src activity for proper signaling to small Rho GTPases.

scholarly journals Signaling for NKT cell development

2005 ◽  
Vol 201 (6) ◽  
pp. 833-836 ◽  
Author(s):  
Christine Borowski ◽  
Albert Bendelac
Keyword(s):  
T Cell ◽  
Critical Role ◽  
Hematopoietic Cells ◽  
Adaptor Protein ◽  
Cell Development ◽  
Thymic Selection ◽  
Nkt Cell ◽  
Cell Lineages ◽  
Receptor Interactions ◽  
Slam Family

New studies demonstrate a critical role for the adaptor protein SAP (SLAM-associated protein) during NKT cell development. By connecting homotypic SLAM family receptor interactions with the FynT Src kinase, SAP may integrate a set of long-standing yet seemingly disparate observations characterizing NKT cell development. In fact, SAP-dependent signaling may underlie the development of multiple unconventional T cell lineages whose thymic selection relies on homotypic interactions between hematopoietic cells.

scholarly journals PLC-γ directly binds activated c-Src, which is necessary for carbachol-mediated inhibition of NHE3 activity in Caco-2/BBe cells

2013 ◽  
Vol 305 (3) ◽  
pp. C266-C275 ◽  
Author(s):  
Nicholas C. Zachos ◽  
Luke J. Lee ◽  
Olga Kovbasnjuk ◽  
Xuhang Li ◽  
Mark Donowitz
Keyword(s):  
Sh2 Domain ◽  
Signaling Proteins ◽  
Multiprotein Complexes ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Inhibitor ◽  
Intracellular Ca ◽  
Direct Binding ◽  
Src Homology

Elevated levels of intracellular Ca2+([Ca2+]i) inhibit Na+/H+exchanger 3 (NHE3) activity in the intact intestine. We previously demonstrated that PLC-γ directly binds NHE3, an interaction that is necessary for [Ca2+]iinhibition of NHE3 activity, and that PLC-γ Src homology 2 (SH2) domains may scaffold Ca2+signaling proteins necessary for regulation of NHE3 activity. [Ca2+]iregulation of NHE3 activity is also c-Src dependent; however, the mechanism by which c-Src is involved is undetermined. We hypothesized that the SH2 domains of PLC-γ might link c-Src to NHE3-containing complexes to mediate [Ca2+]iinhibition of NHE3 activity. In Caco-2/BBe cells, carbachol (CCh) decreased NHE3 activity by ∼40%, an effect abolished with the c-Src inhibitor PP2. CCh treatment increased the amount of active c-Src as early as 1 min through increased Y416phosphorylation. Coimmunoprecipitation demonstrated that c-Src associated with PLC-γ, but not NHE3, under basal conditions, an interaction that increased rapidly after CCh treatment and occurred before the dissociation of PLC-γ and NHE3 that occurred 10 min after CCh treatment. Finally, direct binding to c-Src only occurred through the PLC-γ SH2 domains, an interaction that was prevented by blocking the PLC-γ SH2 domain. This study demonstrated that c-Src 1) activity is necessary for [Ca2+]iinhibition of NHE3 activity, 2) activation occurs rapidly (∼1 min) after CCh treatment, 3) directly binds PLC-γ SH2 domains and associates dynamically with PLC-γ under elevated [Ca2+]iconditions, and 4) does not directly bind NHE3. Under elevated [Ca2+]iconditions, PLC-γ scaffolds c-Src into NHE3-containing multiprotein complexes before dissociation of PLC-γ from NHE3 and subsequent endocytosis of NHE3.

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