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

• Cyclin G-associated kinase: a novel androgen receptor-interacting transcriptional coactivator that is overexpressed in hormone refractory prostate cancer [1].
• Co-immunoprecipitation and Western blotting showed that GAK and cyclin G associate together in vivo [8].
• We previously cloned a rat cDNA encoding GAK, an association partner of cyclin G and CDK5 [9].
• We propose that GAK is a required cofactor for the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells [5].
• The recruitment of GAK is dependent on its PTEN-like domain, which we found binds to phospholipids [7].

Analytical, diagnostic and therapeutic context of GAK

• By the FISH technique, we assigned the chromosomal localization of GAK to 4p16 [9].
• Northern blot analysis showed that GAK is expressed ubiquitously, with the highest level of expression being observed in the testis [9].

References