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Gene Review

GAK  -  cyclin G associated kinase

Homo sapiens

Synonyms: Cyclin-G-associated kinase, DNAJ26, DNAJC26
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Disease relevance of GAK

  • Finally, neo-adjuvant hormone therapy (NHT) tissue microarray analysis demonstrated that GAK expression increased significantly with prostate cancer progression to androgen independence, which suggests a prognostic role for GAK in advanced disease [1].
  • During a 20-year period 1967-86, 476 consecutive cases of severe acute pancreatitis were managed by one surgeon (GAK) and the role and results of surgical intervention in this group were reviewed [2].

High impact information on GAK

  • We investigated epidermal growth factor (EGF) receptor-mediated signaling in cells, in which GAK is down-regulated by small hairpin RNAs [3].
  • Here, we report that down-regulation of GAK by small hairpin RNA has two pronounced effects on EGF receptor signaling: (i) the levels of receptor expression and tyrosine kinase activity go up by >50-fold; and (ii) the spectrum of downstream signaling is significantly changed [3].
  • The alterations resulting from GAK down-regulation can have distinctive biological consequences: In CV1P cells, down-regulation of GAK results in outgrowth of cells in soft agar, raising the possibility that loss of GAK function may promote tumorigenesis [3].
  • Cyclin G-associated kinase (GAK) is a serine/threonine kinase that features high homology outside its kinase domain with auxilin [3].
  • The serine/threonine kinase cyclin G-associated kinase regulates epidermal growth factor receptor signaling [3].

Biological context of GAK

  • Depletion of GAK/auxilin 2 inhibits receptor-mediated endocytosis and recruitment of both clathrin and clathrin adaptors [4].

Anatomical context of GAK

  • Immunolocalization studies suggest that GAK is a cytosolic protein that is concentrated in the perinuclear region; it appears to be highly associated with the trans-Golgi where the budding of clathrin-coated vesicles occurs [5].
  • Western blot analysis shows that GAK is present in rat liver, bovine testes, and bovine brain clathrin-coated vesicles [5].
  • Structurally, depletion of GAK caused a marked reduction in perinuclear clathrin associated with the trans-Golgi network and in the number of clathrin-coated pits on the plasma membrane, and reduced clathrin exchange on the few clathrin-coated pits that remained [4].
  • We have now investigated the effect of knocking down GAK in HeLa cells by vector-based small hairpin RNA [4].
  • Furthermore, we demonstrated that GAK plays a role in the clathrin-dependent trafficking from the trans Golgi network [6].

Physical interactions of GAK

  • Total internal reflectance microscopy was used to determine the timing of GAK binding relative to dynamin and clathrin binding during invagination of clathrin-coated pits [7].

Regulatory relationships of GAK

  • Additionally, GAK enhanced the AR transcriptional response even at low concentrations of androgens, which is relevant to AR activity in androgen-independent prostate cancer [1].

Other interactions of GAK


Analytical, diagnostic and therapeutic context of GAK


  1. Cyclin G-associated kinase: a novel androgen receptor-interacting transcriptional coactivator that is overexpressed in hormone refractory prostate cancer. Ray, M.R., Wafa, L.A., Cheng, H., Snoek, R., Fazli, L., Gleave, M., Rennie, P.S. Int. J. Cancer (2006) [Pubmed]
  2. Surgical intervention in severe acute pancreatitis: 476 cases in 20 years. Kune, G.A., Brough, W. Annals of the Royal College of Surgeons of England. (1989) [Pubmed]
  3. The serine/threonine kinase cyclin G-associated kinase regulates epidermal growth factor receptor signaling. Zhang, L., Gjoerup, O., Roberts, T.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. Depletion of GAK/auxilin 2 inhibits receptor-mediated endocytosis and recruitment of both clathrin and clathrin adaptors. Lee, D.W., Zhao, X., Zhang, F., Eisenberg, E., Greene, L.E. J. Cell. Sci. (2005) [Pubmed]
  5. Role of cyclin G-associated kinase in uncoating clathrin-coated vesicles from non-neuronal cells. Greener, T., Zhao, X., Nojima, H., Eisenberg, E., Greene, L.E. J. Biol. Chem. (2000) [Pubmed]
  6. Multiple roles for cyclin G-associated kinase in clathrin-mediated sorting events. Zhang, C.X., Engqvist-Goldstein, A.E., Carreno, S., Owen, D.J., Smythe, E., Drubin, D.G. Traffic (2005) [Pubmed]
  7. Recruitment dynamics of GAK and auxilin to clathrin-coated pits during endocytosis. Lee, D.W., Wu, X., Eisenberg, E., Greene, L.E. J. Cell. Sci. (2006) [Pubmed]
  8. GAK: a cyclin G associated kinase contains a tensin/auxilin-like domain. Kanaoka, Y., Kimura, S.H., Okazaki, I., Ikeda, M., Nojima, H. FEBS Lett. (1997) [Pubmed]
  9. Structure, expression, and chromosomal localization of human GAK. Kimura, S.H., Tsuruga, H., Yabuta, N., Endo, Y., Nojima, H. Genomics (1997) [Pubmed]
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