Alternative titles; symbols
HGNC Approved Gene Symbol: NCK1
Cytogenetic location: 3q22.3 Genomic coordinates (GRCh38): 3:136,862,208-136,951,606 (from NCBI)
NCK1 belongs to a family of adaptor protein composed exclusively of Src homology-2 (SH2) and -3 (SH3) domains. These proteins function by coupling tyrosine phosphorylation via SH2 domains to downstream effectors through SH3 domains (Chen et al., 1998).
Vorobieva et al. (1995) stated that the NCK and ARF4 (601177) genes were cloned by virtue of their presence in NotI-linking clones from chromosome 3.
Chen et al. (1998) found by Northern blot analysis that NCK-alpha and NCK-beta (604930) were expressed in almost all tissues examined, with variation in relative abundance among different tissues. Generation of NCK-alpha- and NCK-beta-specific antibodies allowed detection of both proteins in a wide range of cell types.
Chen et al. (1998) overexpressed HA-tagged NCK-alpha and NCK-beta in NIH 3T3 cells and found that NCK-beta inhibited, while NCK-alpha enhanced, epidermal growth factor (EGF; 131530)-stimulated DNA synthesis. NCK-beta strongly inhibited and NCK-alpha slightly inhibited EGF- and platelet-derived growth factor (PDGF; see 190040)-induced DNA synthesis.
Eden et al. (2002) reported a mechanism by which RAC1 (602048) and the adaptor protein NCK activate actin nucleation through WAVE1 (605035). WAVE1 exists in a heterotetrameric complex that includes orthologs of human PIR121 (606323), NAP125 (604891), and HSPC300 (C3ORF10; 611183). Whereas recombinant WAVE1 is constitutively active, the WAVE1 complex is inactive. Eden et al. (2002) proposed that Rac1 and Nck cause dissociation of the WAVE1 complex, which releases active WAVE1-HSPC300 and leads to actin nucleation. Eden et al. (2002) also determined that ABI2 (606442) interacts with WAVE1 and appears to remain associated with the NAP125-PIR121 subcomplex upon dissociation of the WAVE1 complex.
Kremer et al. (2007) showed that knockdown of SEPT2 (601506), SEPT6 (300683), and SEPT7 (603151) in HeLa cells caused actin stress fibers to disintegrate and cells to lose polarity. They found that these septins acted through SOCS7 (608788) to restrict nuclear accumulation of NCK. In the absence of septin filaments, SOCS7 recruited NCK into the nucleus. Moreover, depletion of NCK from the cytoplasm triggered dissolution of actin stress fibers and loss of cell polarity. Kremer et al. (2007) also showed that the association between septins, SOCS7, and NCK played a role in the DNA damage checkpoint response. NCK entered the nucleus following DNA damage and was required for ultraviolet (UV)-induced cell cycle arrest. Furthermore, nuclear NCK was essential for activation of p53 (TP53; 191170) in response to UV-induced DNA damage. Kremer et al. (2007) concluded that septins, SOCS7, and NCK are part of a signaling pathway that couples regulation of the DNA damage response to the cytoskeleton.
Li et al. (2012) showed that interactions between diverse synthetic, multivalent macromolecules (including multidomain proteins and RNA) produce sharp liquid-liquid-demixing phase separations, generating micrometer-sized liquid droplets in aqueous solution. This macroscopic transition corresponds to a molecular transition between small complexes and large, dynamic supramolecular polymers. The concentrations needed for phase transition are directly related to the valency of the interacting species. In the case of the actin-regulatory protein N-WASP (605056) interacting with its established biologic partners NCK and phosphorylated nephrin (602716), the phase transition corresponds to a sharp increase in activity towards an actin nucleation factor, the ARP2/3 complex (see 604221). The transition is governed by the degree of phosphorylation of nephrin, explaining how this property of the system can be controlled to regulatory effect by kinases. Li et al. (2012) concluded that the widespread occurrence of multivalent systems suggests that phase transitions may be used to spatially organize and biochemically regulate information throughout biology.
By fluorescence in situ hybridization, Vorobieva et al. (1995) mapped the melanoma NCK protein gene to 3q21. Huebner et al. (1994) mapped the NCK gene to 3q21 by isotopic in situ hybridization.
Fawcett et al. (2007) stated that mice lacking either Nck1 or Nck2 are viable, whereas double mutants die at embryonic day 9.5. They developed a line of mice with Nck1 knockout coupled with conditional Nck2 deletion in the nervous system; Nck2 expression was retained in nonneural tissues. These Nck-deficient mice showed a hopping gait and defects in response of corticospinal tract neurons to midline cues. Isolated spinal cord preparations showed an altered pattern of flexor and extensor muscle activation, and there were defects in spinal interneurons. These phenotypes are similar to those exhibited by Epha4 (602188)-null mice, suggesting that Nck adaptors couple tyrosine phosphorylation guidance signals to cytoskeletal events required for the ipsilateral projections of spinal cord neurons and for normal limb movement.
Chen, M., She, H., Davis, E. M., Spicer, C. M., Kim, L., Ren, R., LeBeau, M. M., Li, W. Identification of Nck family genes, chromosomal localization, expression, and signaling specificity. J. Biol. Chem. 273: 25171-25178, 1998. [PubMed: 9737977] [Full Text: https://doi.org/10.1074/jbc.273.39.25171]
Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M., Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418: 790-793, 2002. [PubMed: 12181570] [Full Text: https://doi.org/10.1038/nature00859]
Fawcett, J. P., Georgiou, J., Ruston, J., Bladt, F., Sherman, A., Warner, N., Saab, B. J., Scott, R., Roder, J. C., Pawson, T. Nck adaptor proteins control the organization of neuronal circuits important for walking. Proc. Nat. Acad. Sci. 104: 20973-20978, 2007. [PubMed: 18093944] [Full Text: https://doi.org/10.1073/pnas.0710316105]
Huebner, K., Kastury, K., Druck, T., Salcini, A. E., Lanfrancone, L., Pelicci, G., Lowenstein, E., Li, W., Park, S.-H., Cannizzaro, L., Pelicci, P. G., Schlessinger, J. Chromosome locations of genes encoding human signal transduction adapter proteins, Nck (NCK), Shc (SHC1), and Grb2 (GRB2). Genomics 22: 281-287, 1994. [PubMed: 7806213] [Full Text: https://doi.org/10.1006/geno.1994.1385]
Kremer, B. E., Adang, L. A., Macara, I. G. Septins regulate actin organization and cell-cycle arrest through nuclear accumulation of NCK mediated by SOCS7. Cell 130: 837-850, 2007. [PubMed: 17803907] [Full Text: https://doi.org/10.1016/j.cell.2007.06.053]
Li, P., Banjade, S., Cheng, H.-C., Kim, S., Chen, B., Guo, L., Llaguno, M., Hollingsworth, J. V., King, D. S., Banani, S. F., Russo, P. S., Jiang, Q.-X., Nixon, B. T., Rosen, M. K. Phase transitions in the assembly of multivalent signalling proteins. Nature 483: 336-340, 2012. [PubMed: 22398450] [Full Text: https://doi.org/10.1038/nature10879]
Vorobieva, N., Protopopov, A., Protopopov, M., Kashuba, V., Allikmets, R. L., Modi, W., Zabarovsky, E. R., Klein, G., Kisselev, L., Graphodatsky, A. Localization of human ARF2 and NCK genes and 13 other NotI-linking clones to chromosome 3 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 68: 91-94, 1995. [PubMed: 7956370] [Full Text: https://doi.org/10.1159/000133898]