Disease relevance of NCK1

• Two human genes containing NotI sites, ADP-ribosylation factor (ARF2) and melanoma NCK protein, were mapped by fluorescence in situ hybridization to 3p21.2-->p21.1 and 3q21, respectively [1].
• Several microbial pathogens including enteropathogenic E. coli (EPEC) exploit mammalian tyrosine-kinase signaling cascades to recruit Nck adaptor proteins and activate N-WASP-Arp2/3-mediated actin assembly [2].
• We hypothesize that the association between TF C alleles and lung cancer may be secondary and dependent on linkage disequilibrium with allelic variants of newly discovered tumor-associated genes known to map to the same position (3q21) as TF, e.g. NCK and H-RYK [3].

High impact information on NCK1

• Two papers, one in Nature (Jones et al., 2006) and the other in the Journal of Clinical Investigation (Verma et al., 2006) show that Nck adaptor proteins connect phosphorylated nephrin with actin polymerization in podocyte foot processes, structures important for slit-diaphragm formation in the kidney [4].
• In contrast, a mutant Dok (DokY361F), in which Tyr361 was replaced by phenylalanine, failed to bind NCK but partially retained the ability to bind rasGAP in response to insulin [5].
• Two of these proteins represented the tyrosine kinase fyn and the mouse homologue of phospholipase C-gamma 1, whereas two genes encoded proteins similar to v-crk and NCK [6].
• We also found that NCK binds directly to the guanine nucleotide exchange factor SOS [7].
• We found that in NIH 3T3 cells, NCK strongly activates this promoter [7].

Biological context of NCK1

• CONCLUSION: These results demonstrate that localization of Pak1 to the membrane in the absence of other signals is sufficient for its activation, and imply that the Nck adaptor protein could function to link changes in tyrosine phosphorylation of cellular proteins to the Cdc42/Pak signaling pathway [8].
• To identify potential downstream effectors of NCK we screened a bacterial expression library to isolate proteins that bind its SH3 domains [9].
• Although the association of NCK with activated receptor protein-tyrosine kinases, via its SH2 domain, implicates NCK as a mediator of growth factor-induced signal transduction, little is known about the pathway(s) downstream of NCK recruitment [9].

Anatomical context of NCK1

• VEGF stimulated the tyrosine phosphorylation of the SH2 domain-containing signaling proteins NCK and CRK in human umbilical vein endothelial cells [10].
• We have previously shown that overexpression of the SH2- and SH3-containing Nck adaptor protein causes transformation of mammalian fibroblast [11].
• These results suggest that the Nck adaptor protein interacts with key signaling molecules and may play an important role in activation of T lymphocytes [12].
• Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes [13].

Associations of NCK1 with chemical compounds

• A novel ligand for SH3 domains. The Nck adaptor protein binds to a serine/threonine kinase via an SH3 domain [11].
• The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains [14].
• The first proline-rich region of PAK that binds to an SH3 domain from the adapter protein NCK was responsible for these dominant-negative effects [15].

Physical interactions of NCK1

• SOCS7 interacts with septins and NCK through distinct domains [16].

Other interactions of NCK1

• Additionally, NCK and SHC genes were more narrowly localized by chromosomal in situ hybridization [17].
• Based on this binding motif, we identify potential new binding partners of Nck1 and Nck2 and confirm this experimentally for the Arf-GAP GIT1 [14].
• Tyrosine phosphorylation of p62Dok resulted in its complex formation with the Ras GTPase-activating protein (RasGAP) and the Nck adaptor protein [18].
• Fluorescent polarization measurements using soluble peptides and purified SH3 domains demonstrated that several SH3 domains, including those from growth factor receptor-bound protein 2 (Grb2), NCK, and phospholipase C (PLC)-gamma1, bound with moderate affinities (10-100 microm) to a group of non-conventional peptides [19].
• The SH2 domain of the Nck adaptor can bind tyrosine-phosphorylated proteins, while its SH3 domains can modulate actin polymerization by interacting with effectors such as WASp/Scar family proteins [20].

References