# GAK

## Overview
GAK, or cyclin G-associated kinase, is a gene that encodes a multifunctional serine/threonine kinase involved in various cellular processes, including clathrin-mediated endocytosis and membrane trafficking. The protein encoded by this gene, also referred to as cyclin G-associated kinase, plays a critical role in the phosphorylation of clathrin adaptors and interacts with several other proteins to facilitate cellular signaling and trafficking. Structurally, GAK features a kinase domain integral to its function and interaction with inhibitors, and it exhibits a bi-lobal architecture typical of kinases. This kinase is not only pivotal in cellular trafficking but also has implications in clinical contexts, particularly in neurodegenerative diseases such as Parkinson's disease (Zhang2005Multiple; Dumitriu2011Cyclin-G-associated; Lee2005Depletion).

## Structure
The molecular structure of cyclin G-associated kinase (GAK) is characterized by a typical bi-lobal kinase architecture, which includes both N- and C-lobes that are highly conserved across the kinase family. The kinase domain specifically spans residues 14-351, with an activation segment ranging from Asp 181 to Ile 230. This segment is noted to be largely disordered and capable of binding to the upper kinase lobe of an interacting protomer, indicating a specific interaction pattern within the protein structure (Chaikuad2014Structure).

GAK exhibits several distinct domains crucial for its function and regulation. These include an N-terminal tensin domain, a clathrin-binding domain, and a J-domain, which are homologous with auxillin. The kinase domain is involved in the binding of clinically approved drugs like ponatinib, dasatinib, bosutinib, sunitinib, and gefitinib, which stabilize the protein through shifts in melting temperature indicative of strong inhibitor binding (Chaikuad2014Structure).

In terms of quaternary structure, GAK can dimerize in solution, although this dimerization is weak and was not detected in gel-filtration experiments. The crystallization of the GAK kinase domain revealed that two kinase molecules occupy the asymmetric unit of the hexagonal unit cell in a head-to-toe arrangement (Chaikuad2014Structure).

## Function
GAK, or cyclin G-associated kinase, is a multifunctional serine/threonine kinase that plays a pivotal role in clathrin-mediated endocytosis (CME) and membrane trafficking. It is essential for the phosphorylation of clathrin adaptors AP-1 and AP-2, which are crucial for the formation and function of clathrin-coated vesicles (CCVs) involved in the internalization of receptors such as the transferrin and epidermal growth factor receptors (Zhang2005Multiple; Lee2005Depletion). GAK also interacts with the Hsc70 family of heat-shock proteins to facilitate the uncoating of CCVs, a critical step for recycling clathrin and maintaining efficient endocytosis (Lee2005Depletion).

In addition to its role in endocytosis, GAK is involved in trafficking from the trans-Golgi network to endosomes and lysosomes, impacting the maturation of enzymes like cathepsin D, which is necessary for lysosomal function (Kametaka2007Canonical). This kinase is also implicated in the regulation of receptor signaling pathways, notably influencing the activity of the epidermal growth factor receptor (EGFR) by modulating its expression and activity upon depletion (Zhang2005Multiple).

Furthermore, GAK's kinase activity, while crucial in some contexts, appears dispensable for certain endocytic functions, such as transferrin uptake, suggesting overlapping roles with other proteins or alternative functions beyond its kinase activity (Zhang2005Multiple). This indicates a complex regulatory mechanism where GAK may have both kinase-dependent and independent roles in cellular trafficking and signal transduction.

## Clinical Significance
GAK, or cyclin G associated kinase, has been implicated in the pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the brain. Mutations and variations in the GAK gene have been associated with both familial and sporadic forms of PD. A specific single nucleotide polymorphism (SNP) in the GAK gene, rs1564282, has been identified as a significant risk factor for PD in various populations, showing a genome-wide level of significance and association with higher levels of SNCA expression, which is linked to increased PD risk (Ma2015Quantitative; Dumitriu2011Cyclin-G-associated). 

Research has shown that reduced expression of GAK exacerbates the toxicity of A53T a-synuclein to dopaminergic neurons, suggesting that GAK plays a crucial role in modulating a-synuclein levels and toxicity (Dumitriu2011Cyclin-G-associated). Additionally, GAK interacts with cathepsin D (CTSD), a lysosomal enzyme involved in a-synuclein degradation. Mutations in CTSD lead to a-synuclein accumulation, suggesting a pathway involving GAK and CTSD in PD (Dumitriu2011Cyclin-G-associated). 

These findings highlight the clinical significance of GAK in PD and suggest it as a potential therapeutic target for managing the disease.

## Interactions
GAK, or cyclin G associated kinase, interacts with a variety of proteins and nucleic acids, playing a crucial role in cellular processes such as membrane trafficking and cell cycle regulation. GAK has been shown to interact with clathrin and the Hsc70 chaperone, facilitating the uncoating of clathrin-coated vesicles. This interaction is mediated by the J-domain of GAK, which is essential for stimulating the ATPase activity of Hsc70 (Greener2000Role; Umeda2000Identification). Additionally, GAK competes with auxilin for binding to clathrin, suggesting overlapping binding sites on the clathrin heavy chain (Umeda2000Identification).

GAK also interacts with adaptor proteins AP-1 and AP-2, crucial for vesicular trafficking. The binding to AP-2 is mediated by the 'DPF' motif in GAK, while the g-appendage domain of AP-1 binds to GAK and competes with intact AP-1 for binding (Umeda2000Identification). Furthermore, GAK interacts with the androgen receptor (AR), particularly binding strongly to the AR ligand-binding domain (AR.LBD) and is involved in hormone signaling pathways (Ray2005Cyclin).

In the context of cellular signaling, GAK phosphorylates the T104 residue of the PP2A B'γ subunit, enhancing the phosphatase activity of PP2A, which plays a role in the dephosphorylation of CHK2-pT68 after DNA damage (Naito2012Cyclin). This interaction highlights GAK's role in regulating protein phosphatase activity and influencing cell cycle progression and DNA damage response.


## References


[1. (Chaikuad2014Structure) Apirat Chaikuad, Tracy Keates, Cécile Vincke, Melanie Kaufholz, Michael Zenn, Bastian Zimmermann, Carlos Gutiérrez, Rong-guang Zhang, Catherine Hatzos-Skintges, Andrzej Joachimiak, Serge Muyldermans, Friedrich W. Herberg, Stefan Knapp, and Susanne Müller. Structure of cyclin g-associated kinase (gak) trapped in different conformations using nanobodies. Biochemical Journal, 459(1):59–69, March 2014. URL: http://dx.doi.org/10.1042/bj20131399, doi:10.1042/bj20131399. (72 citations) 10.1042/bj20131399](https://doi.org/10.1042/bj20131399)

[2. (Kametaka2007Canonical) Satoshi Kametaka, Kengo Moriyama, Patricia V. Burgos, Evan Eisenberg, Lois E. Greene, Rafael Mattera, and Juan S. Bonifacino. Canonical interaction of cyclin g–associated kinase with adaptor protein 1 regulates lysosomal enzyme sorting. Molecular Biology of the Cell, 18(8):2991–3001, August 2007. URL: http://dx.doi.org/10.1091/mbc.E06-12-1162, doi:10.1091/mbc.e06-12-1162. (65 citations) 10.1091/mbc.E06-12-1162](https://doi.org/10.1091/mbc.E06-12-1162)

[3. (Naito2012Cyclin) Yoko Naito, Hiroyuki Shimizu, Takashi Kasama, Jun Sato, Hiroe Tabara, Ayumi Okamoto, Norikazu Yabuta, and Hiroshi Nojima. Cyclin g-associated kinase regulates protein phosphatase 2a by phosphorylation of its b’γ subunit. Cell Cycle, 11(3):604–616, February 2012. URL: http://dx.doi.org/10.4161/cc.11.3.19114, doi:10.4161/cc.11.3.19114. (24 citations) 10.4161/cc.11.3.19114](https://doi.org/10.4161/cc.11.3.19114)

[4. (Zhang2005Multiple) Claire X. Zhang, Åsa E. Y. Engqvist‐Goldstein, Sebastien Carreno, David J. Owen, Elizabeth Smythe, and David G. Drubin. Multiple roles for cyclin g‐associated kinase in clathrin‐mediated sorting events. Traffic, 6(12):1103–1113, September 2005. URL: http://dx.doi.org/10.1111/j.1600-0854.2005.00346.x, doi:10.1111/j.1600-0854.2005.00346.x. (83 citations) 10.1111/j.1600-0854.2005.00346.x](https://doi.org/10.1111/j.1600-0854.2005.00346.x)

[5. (Umeda2000Identification) Akiko Umeda, Anika Meyerholz, and Ernst Ungewickell. Identification of the universal cofactor (auxilin 2) in clathrin coat dissociation. European Journal of Cell Biology, 79(5):336–342, May 2000. URL: http://dx.doi.org/10.1078/s0171-9335(04)70037-0, doi:10.1078/s0171-9335(04)70037-0. (141 citations) 10.1078/s0171-9335(04)70037-0](https://doi.org/10.1078/s0171-9335(04)70037-0)

[6. (Ray2005Cyclin) Mira R. Ray, Latif A. Wafa, Helen Cheng, Robert Snoek, Ladan Fazli, Martin Gleave, and Paul S. Rennie. Cyclin g‐associated kinase: a novel androgen receptor‐interacting transcriptional coactivator that is overexpressed in hormone refractory prostate cancer. International Journal of Cancer, 118(5):1108–1119, December 2005. URL: http://dx.doi.org/10.1002/ijc.21469, doi:10.1002/ijc.21469. (58 citations) 10.1002/ijc.21469](https://doi.org/10.1002/ijc.21469)

[7. (Dumitriu2011Cyclin-G-associated) A. Dumitriu, C. D. Pacheco, J. B. Wilk, K. E. Strathearn, J. C. Latourelle, S. Goldwurm, G. Pezzoli, J.-C. Rochet, S. Lindquist, and R. H. Myers. Cyclin-g-associated kinase modifies -synuclein expression levels and toxicity in parkinson’s disease: results from the genepd study. Human Molecular Genetics, 20(8):1478–1487, January 2011. URL: http://dx.doi.org/10.1093/hmg/ddr026, doi:10.1093/hmg/ddr026. (78 citations) 10.1093/hmg/ddr026](https://doi.org/10.1093/hmg/ddr026)

[8. (Greener2000Role) Tsvika Greener, Xiaohong Zhao, Hiroshi Nojima, Evan Eisenberg, and Lois E. Greene. Role of cyclin g-associated kinase in uncoating clathrin-coated vesicles from non-neuronal cells. Journal of Biological Chemistry, 275(2):1365–1370, January 2000. URL: http://dx.doi.org/10.1074/jbc.275.2.1365, doi:10.1074/jbc.275.2.1365. (203 citations) 10.1074/jbc.275.2.1365](https://doi.org/10.1074/jbc.275.2.1365)

[9. (Ma2015Quantitative) Ze-Gang Ma, Feng He, and Jian Xu. Quantitative assessment of the association between gak rs1564282 c/t polymorphism and the risk of parkinson’s disease. Journal of Clinical Neuroscience, 22(7):1077–1080, July 2015. URL: http://dx.doi.org/10.1016/j.jocn.2014.12.014, doi:10.1016/j.jocn.2014.12.014. (8 citations) 10.1016/j.jocn.2014.12.014](https://doi.org/10.1016/j.jocn.2014.12.014)

[10. (Lee2005Depletion) Dong-won Lee, Xiaohong Zhao, Fang Zhang, Evan Eisenberg, and Lois E. Greene. Depletion of gak/auxilin 2 inhibits receptor-mediated endocytosis and recruitment of both clathrin and clathrin adaptors. Journal of Cell Science, 118(18):4311–4321, September 2005. URL: http://dx.doi.org/10.1242/jcs.02548, doi:10.1242/jcs.02548. (71 citations) 10.1242/jcs.02548](https://doi.org/10.1242/jcs.02548)