NCK2

Last update 08 May 2025

Basic Info

Synonyms

Cytoplasmic protein NCK2, GRB4, Growth factor receptor-bound protein 4

+ [5]

Introduction

Adapter protein which associates with tyrosine-phosphorylated growth factor receptors or their cellular substrates. Maintains low levels of EIF2S1 phosphorylation by promoting its dephosphorylation by PP1. Plays a role in ELK1-dependent transcriptional activation in response to activated Ras signaling.

100 Clinical Results associated with NCK2

100 Translational Medicine associated with NCK2

0 Patents (Medical) associated with NCK2

149

Literatures (Medical) associated with NCK2

21 Jan 2025·Clinical and Experimental Immunology

Nck1 regulates the in vitro development of human regulatory T cells through AKT pathway

Article

Author: Sayasathid, Jarun ; Thatsakorn, Kanthachat ; Ngoenkam, Jatuporn ; Nuiyen, Aussanee ; Thapmongkol, Siraphop ; Sanguansermsri, Donruedee ; Pongcharoen, Sutatip

AbstractT cell receptor (TCR) signalling is crucial in determining the fate of thymocyte differentiation in the thymus. The high-avidity interaction between TCR and self-peptide-MHC complexes induces development of regulatory T cells (Tregs), lineage commitment for which is controlled by expression of transcription factor Forkhead box P3 (FoxP3). The non-catalytic region of the tyrosine kinase (Nck) comprises two members, Nck1 and Nck2, with Nck1 playing a dominant role in TCR-mediated T cell activation and function. Nck’s role, while established in thymocyte development, remains unelucidated in development of Tregs. In this study, we aimed to determine the function of Nck1 in the in vitro development and differentiation of human thymocytes. Human thymocytes were transfected with shRNA plasmid to silence Nck1 expression. The number of FoxP3+ Tregs decreased noticeably in Nck1 knockdown thymocytes after co-cultivation with myeloid dendritic cells (mDCs) and thymic epithelial cells for 14 days. Furthermore, decreased phosphorylation of AKT and FoxO1 was observed in Nck1-silenced thymocytes, in association with reduced FoxO1 nuclear localization. Taken together, these findings identify the pivotal role of Nck1 in Treg development.

01 Dec 2024·Alzheimer's & Dementia

An AD‐associated variant in TTC3 alters the actin cytoskeleton organization and synaptic function in iPSC‐derived forebrain neurons

Article

Author: Duarte, Carolina L. ; Dykxhoorn, Derek M. ; Lambert, Caleb Avery ; Van Booven, Derek ; Griswold, Anthony J. ; Cukier, Holly N. ; DeRosa, Brooke A. ; Coombs, Lauren ; Pericak‐Vance, Margaret A

AbstractBackgroundWe identified the missense variant Ser1038Cys (rs377155188) in the tetratricopeptide repeat domain 3 (TTC3) gene that segregate in a non‐Hispanic white late onset Alzheimer disease (LOAD) family. This variant is predicted to be deleterious and extremely rare (MAF<0.01%). Expression of TTC3 is decreased in the brains of LOAD patients and negatively correlated with AD neuropathology.MethodsCRISPR/Cas9 genome editing was used to introduce the TTC3 Ser1038Cys variant into a control iPSC line. induced pluripotent stem cells (iPSCs) were developed that were homozygous for the TTC3 variant and validated for pluripotency. To understand the mechanism(s) by which this TTC3 variant may contribute to LOAD risk, this isogenic pair of edited and unedited iPSCs was differentiated into forebrain neurons and assessed for the cellular, molecular, and transcriptional consequences of this variant, including neuronal morphology, synaptic functionality, and vesicular trafficking.ResultsNeuronal progenitor cells (NPCs) derived from the isogenic iPSC lines showed that TTC3 variant‐bearing cells had elevated migration rates compared to their wild type counterparts as assessed by wound healing assays. Forebrain neurons bearing the Ser1038Cys variant showed elongated neurites and higher numbers of branchpoints compared to the wild type neurons phenocopying the effect of TTC3 loss of function analysis (siRNA‐mediated silencing of TTC3 in mouse neurons). This phenotype could be reversed using small molecule modulators of actin polymerization. Immunoblot analysis showed alterations in the expression of pre‐ and post‐synaptic markers in the TTC3 Ser1038Cys neurons compared to control neurons. RNA‐seq analysis of day 70 neurons identified 978 differentially expressed protein‐coding genes (FDR<0.05), including known AD genes (BACE1, A2M, INPP5F, UNC5C) and genes in AD GWAS loci (ADAMTS1, MAF, NCK2). Pathway analysis identified differential expression in PI3K‐Akt signaling pathway, as well as genes involved in axon guidance, the GABAergic synapse, and the Wnt signaling pathways.ConclusionsThe results of these studies suggest that the TTC3 p.Ser1038Cys variant causes a loss of function leading to alterations in neurite outgrowth, branching, and synapse formation, phenotypes consistent with alterations in actin stability. These studies in iPSC‐derived neurons implicate alterations in actin as potential mechanisms by which TTC3 may contribute to LOAD risk.

16 Oct 2024·Biochemical Journal

Adapting to change: resolving the dynamic and dual roles of NCK1 and NCK2

Review

Author: Shata, Erka ; Bisson, Nicolas ; Teyssier, Valentine ; Williamson, Casey R. ; Jones, Nina ; Rosen, Stephanie P.

Adaptor proteins play central roles in the assembly of molecular complexes and co-ordinated activation of specific pathways. Through their modular domain structure, the NCK family of adaptor proteins (NCK1 and NCK2) link protein targets via their single SRC Homology (SH) 2 and three SH3 domains. Classically, their SH2 domain binds to phosphotyrosine motif-containing receptors (e.g. receptor tyrosine kinases), while their SH3 domains bind polyproline motif-containing cytoplasmic effectors. Due to these functions being established for both NCK1 and NCK2, their roles were inaccurately assumed to be redundant. However, in contrast with this previously held view, NCK1 and NCK2 now have a growing list of paralog-specific functions, which underscores the need to further explore their differences. Here we review current evidence detailing how these two paralogs are unique, including differences in their gene/protein regulation, binding partners and overall contributions to cellular functions. To help explain these contrasting characteristics, we then discuss SH2/SH3 structural features, disordered interdomain linker regions and post-translational modifications. Together, this review seeks to highlight the importance of distinguishing NCK1 and NCK2 in research and to pave the way for investigations into the origins of their interaction specificity.

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NCK2

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