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Last update 08 May 2025

GAK

Last update 08 May 2025

Basic Info

Synonyms

auxilin-2, cyclin G associated kinase, Cyclin-G-associated kinase

+ [2]

Introduction

Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1 (PubMed:10625686). May play a role in clathrin-mediated endocytosis and intracellular trafficking, and in the dynamics of clathrin assembly/disassembly (PubMed:18489706).

Drugs associated with GAK

GAK inhibitors(KU Leuven)

Target

GAK

Mechanism

GAK inhibitors

Active Org.

Katholieke Universiteit Leuven

Originator Org.-

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

EphA2/GAK inhibitors(Structural Genomics Consortium)

Target

EphA2 x GAK

Mechanism

EphA2 antagonists [+1]

Active Org.

Structural Genomics Consortium

Originator Org.

Structural Genomics Consortium

Active Indication

Dengue

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SGC-GAK-1

Target

GAK

Mechanism

GAK inhibitors

Active Org.-

Originator Org.

The University of North Carolina at Chapel Hill

Active Indication-

Inactive Indication-

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GAK

100 Translational Medicine associated with GAK

0 Patents (Medical) associated with GAK

195

Literatures (Medical) associated with GAK

31 Dec 2025·ASN Neuro

New Atg9 Phosphorylation Sites Regulate Autophagic Trafficking in Glia

Article

Author: Cheng, Yi-Hsuan ; Lee, Yi-Hua ; Zhang, Shiping ; Ho, Margaret S. ; Wang, Linfang ; Wang, Honglei ; Lin, Chia-Ching ; Lin, Yu-Tung ; Yi, Shuanglong ; Tsai, Yu-Ting

We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase, in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. The enhanced Atg9 phosphorylation in the absence of dAux promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phosphomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. In relation to pathophysiology, Atg9 phosphorylation at T62 and T69 contributes to dopaminergic neurodegeneration and locomotor dysfunction in a Drosophila PD model. Notably, increased expression of the master autophagy regulator Atg1 promotes dAux-Atg9 interaction. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.

04 May 2025·Autophagy

Drosophila aux orchestrates the phosphorylation-dependent assembly of the lysosomal V-ATPase in glia and contributes to SNCA/α-synuclein degradation

Article

Author: Tsai, Yu-Ting ; Ho, Margaret S ; Lee, Yi-Hua ; Liu, Chang ; Wang, Linfang ; Zhang, Shiping ; Yi, Shuanglong ; Yan, Wei ; Cheng, Yi-Hsuan ; Li, Shuhua ; Liu, Yang ; Wang, Honglei ; Lin, Yu-Tung ; Lin, Chia-Ching ; He, Kai-Wen ; Wang, Ruiqi

Glia contribute to the neuropathology of Parkinson disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating SNCA/α-syn (synuclein alpha) inclusions, remains elusive. Here we present evidence that aux (auxilin), the Drosophila homolog of the PD risk factor GAK (cyclin G associated kinase), regulates the lysosomal degradation of SNCA/α-syn in glia. Lack of glial GAK/aux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including SNCA/α-syn. Whereas SNCA/α-syn accumulates prominently in lysosomes devoid of glial aux, levels of injected SNCA/α-syn preformed fibrils are further enhanced in the absence of microglial GAK. Mechanistically, aux mediates phosphorylation at the serine 543 of Vha44, the V₁ C subunit of the vacuolar-type H⁺-translocating ATPase (V-ATPase), and regulates its assembly to control proper acidification of the lysosomal milieu. Expression of Vha44, but not the Vha44 variant lacking S543 phosphorylation, restores lysosome acidity, locomotor deficits, and DA neurodegeneration upon glial aux depletion, linking this pathway to PD. Our findings identify a phosphorylation-dependent switch controlling V-ATPase assembly for lysosomal SNCA/α-syn degradation in glia. Targeting the clearance of glial SNCA/α-syn inclusions via this lysosomal pathway could potentially be a therapeutic approach to ameliorate the disease progression in PD.Abbreviation: aux: auxilin; GAK: cyclin G associated kinase; LTG: LysoTracker Green; LTR: LysoTracker Red; MR: Magic Red; PD: Parkinson disease; SNCA/a-syn: synuclein alpha; V-ATPase: vacuolar-type H⁺-translocating ATPase.

01 Apr 2025·Neurological Sciences

Genetic mutations in kinases: a comprehensive review on marketed inhibitors and unexplored targets in Parkinson's disease

Review

Author: Sahu, Sanjeev Kumar ; Raina, Jeevika ; Wadhwa, Pankaj ; Raza, Amir

This comprehensive review navigates the landscape of genetic mutations in kinases, offering a thorough examination of both marketed inhibitors and unexplored targets in the context of Parkinson's Disease (PD). Although existing treatments for PD primarily center on symptom management, progress in comprehending the molecular foundations of the disease has opened avenues for targeted therapeutic approaches. This review encompasses an in-depth analysis of four key kinases-PINK1, LRRK2, GAK, and PRKRA-revealing that LRRK2 has garnered the most attention with a plethora of marketed inhibitors. However, the study underscores notable gaps in the exploration of inhibitors for PINK1, GAK, and a complete absence for PRKRA. The observed scarcity of inhibitors for these kinases emphasizes a significant area of untapped potential in PD therapeutics. By drawing attention to these unexplored targets, the review highlights the urgent need for focused research and drug development efforts to diversify the therapeutic landscape, potentially providing novel interventions for halting or slowing the progression of PD.

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