Sinner or Saint?: Nck Adaptor Proteins in Vascular Biology

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Jun 14

PMID 34124074

Citations 7

Authors

Mabruka Alfaidi

Matthew L Scott

Anthony Wayne Orr

Affiliations

Soon will be listed here.

Abstract

The Nck family of modular adaptor proteins, including Nck1 and Nck2, link phosphotyrosine signaling to changes in cytoskeletal dynamics and gene expression that critically modulate cellular phenotype. The Nck SH2 domain interacts with phosphotyrosine at dynamic signaling hubs, such as activated growth factor receptors and sites of cell adhesion. The Nck SH3 domains interact with signaling effectors containing proline-rich regions that mediate their activation by upstream kinases. In vascular biology, Nck1 and Nck2 play redundant roles in vascular development and postnatal angiogenesis. However, recent studies suggest that Nck1 and Nck2 differentially regulate cell phenotype in the adult vasculature. Domain-specific interactions likely mediate these isoform-selective effects, and these isolated domains may serve as therapeutic targets to limit specific protein-protein interactions. In this review, we highlight the function of the Nck adaptor proteins, the known differences in domain-selective interactions, and discuss the role of individual Nck isoforms in vascular remodeling and function.

Citing Articles

Modulating PAK1: Accessory Proteins as Promising Therapeutic Targets.

Mirzaiebadizi A, Shafabakhsh R, Ahmadian M Biomolecules. 2025; 15(2).

PMID: 40001545 PMC: 11852631. DOI: 10.3390/biom15020242.

A novel function for α-synuclein as a regulator of NCK2 in olfactory bulb: implications for its role in olfaction.

Ren J, Wu C, Zeng M, Qu M, Gao G, Chen N Cell Biosci. 2024; 14(1):139.

PMID: 39543759 PMC: 11566155. DOI: 10.1186/s13578-024-01313-6.

Functional Classification and Interaction Selectivity Landscape of the Human SH3 Domain Superfamily.

Kazemein Jasemi N, Mehrabipour M, Magdalena Estirado E, Brunsveld L, Dvorsky R, Ahmadian M Cells. 2024; 13(2).

PMID: 38275820 PMC: 10814857. DOI: 10.3390/cells13020195.

Syphilis and the host: multi-omic analysis of host cellular responses to provides novel insight into syphilis pathogenesis.

Waugh S, Ranasinghe A, Gomez A, Houston S, Lithgow K, Eshghi A Front Microbiol. 2023; 14:1254342.

PMID: 37795301 PMC: 10546344. DOI: 10.3389/fmicb.2023.1254342.

An Alzheimer's disease risk variant in TTC3 modifies the actin cytoskeleton organization and the PI3K-Akt signaling pathway in iPSC-derived forebrain neurons.

Cukier H, Duarte C, Laverde-Paz M, Simon S, Van Booven D, Miyares A Neurobiol Aging. 2023; 131:182-195.

PMID: 37677864 PMC: 10538380. DOI: 10.1016/j.neurobiolaging.2023.07.007.

References

Latreille M, Larose L . Nck in a complex containing the catalytic subunit of protein phosphatase 1 regulates eukaryotic initiation factor 2alpha signaling and cell survival to endoplasmic reticulum stress. J Biol Chem. 2006; 281(36):26633-44. DOI: 10.1074/jbc.M513556200. View

Guan S, Fan J, Han A, Chen M, Woodley D, Li W . Non-compensating roles between Nckalpha and Nckbeta in PDGF-BB signaling to promote human dermal fibroblast migration. J Invest Dermatol. 2009; 129(8):1909-20. DOI: 10.1038/jid.2008.457. View

Gil D, Schamel W, Montoya M, Sanchez-Madrid F, Alarcon B . Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell. 2002; 109(7):901-12. DOI: 10.1016/s0092-8674(02)00799-7. View

Machida K, Thompson C, Dierck K, Jablonowski K, Karkkainen S, Liu B . High-throughput phosphotyrosine profiling using SH2 domains. Mol Cell. 2007; 26(6):899-915. DOI: 10.1016/j.molcel.2007.05.031. View

Liu Z, Guo X, Jiang Y, Zhang H . NCK2 is significantly associated with opiates addiction in African-origin men. ScientificWorldJournal. 2013; 2013:748979. PMC: 3603435. DOI: 10.1155/2013/748979. View

Desai C, Garrity P, Keshishian H, Zipursky S, Zinn K . The Drosophila SH2-SH3 adapter protein Dock is expressed in embryonic axons and facilitates synapse formation by the RP3 motoneuron. Development. 1999; 126(7):1527-35. DOI: 10.1242/dev.126.7.1527. View

Aitio O, Hellman M, Kesti T, Kleino I, Samuilova O, Paakkonen K . Structural basis of PxxDY motif recognition in SH3 binding. J Mol Biol. 2008; 382(1):167-78. DOI: 10.1016/j.jmb.2008.07.008. View

Meisenhelder J, Hunter T . The SH2/SH3 domain-containing protein Nck is recognized by certain anti-phospholipase C-gamma 1 monoclonal antibodies, and its phosphorylation on tyrosine is stimulated by platelet-derived growth factor and epidermal growth factor treatment. Mol Cell Biol. 1992; 12(12):5843-56. PMC: 360524. DOI: 10.1128/mcb.12.12.5843-5856.1992. View

Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M . Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 2003; 17(15):1835-40. PMC: 196228. DOI: 10.1101/gad.266803. View

10.

Roche S, McGlade J, Jones M, Gish G, Pawson T, Courtneidge S . Requirement of phospholipase C gamma, the tyrosine phosphatase Syp and the adaptor proteins Shc and Nck for PDGF-induced DNA synthesis: evidence for the existence of Ras-dependent and Ras-independent pathways. EMBO J. 1996; 15(18):4940-8. PMC: 452231. View

11.

Kebache S, Zuo D, Chevet E, Larose L . Modulation of protein translation by Nck-1. Proc Natl Acad Sci U S A. 2002; 99(8):5406-11. PMC: 122782. DOI: 10.1073/pnas.082483399. View

12.

McCarty J . The Nck SH2/SH3 adaptor protein: a regulator of multiple intracellular signal transduction events. Bioessays. 1999; 20(11):913-21. DOI: 10.1002/(SICI)1521-1878(199811)20:11<913::AID-BIES6>3.0.CO;2-T. View

13.

Camenisch T, Molin D, Person A, Runyan R, Gittenberger-de Groot A, McDonald J . Temporal and distinct TGFbeta ligand requirements during mouse and avian endocardial cushion morphogenesis. Dev Biol. 2002; 248(1):170-81. DOI: 10.1006/dbio.2002.0731. View

14.

Shitashige M, Satow R, Jigami T, Aoki K, Honda K, Shibata T . Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010; 70(12):5024-33. DOI: 10.1158/0008-5472.CAN-10-0306. View

15.

Sun C, Wu M, Yuan S . Nonmuscle myosin light-chain kinase deficiency attenuates atherosclerosis in apolipoprotein E-deficient mice via reduced endothelial barrier dysfunction and monocyte migration. Circulation. 2011; 124(1):48-57. PMC: 3136817. DOI: 10.1161/CIRCULATIONAHA.110.988915. View

16.

Potente M, Gerhardt H, Carmeliet P . Basic and therapeutic aspects of angiogenesis. Cell. 2011; 146(6):873-87. DOI: 10.1016/j.cell.2011.08.039. View

17.

Borroto A, Arellano I, Blanco R, Fuentes M, Orfao A, Dopfer E . Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo. J Immunol. 2014; 192(5):2042-53. DOI: 10.4049/jimmunol.1203414. View

18.

Chang H, Li B, Zhang X, Meng X . NCK1-AS1 promotes NCK1 expression to facilitate tumorigenesis and chemo-resistance in ovarian cancer. Biochem Biophys Res Commun. 2019; 522(2):292-299. DOI: 10.1016/j.bbrc.2019.11.014. View

19.

Oeste C, Alarcon B . Editorial: Nck has a knack for T cell differentiation. J Leukoc Biol. 2015; 98(3):297-8. DOI: 10.1189/jlb.2CE0415-181R. View

20.

Clemens J, Ursuliak Z, Clemens K, Price J, Dixon J . A Drosophila protein-tyrosine phosphatase associates with an adapter protein required for axonal guidance. J Biol Chem. 1996; 271(29):17002-5. DOI: 10.1074/jbc.271.29.17002. View