Chemical genetic identification of GAK substrates reveals its role in regulating Na+/K+-ATPase

  title={Chemical genetic identification of GAK substrates reveals its role in regulating Na+/K+-ATPase},
  author={Amy Lin and Kalbinder K. Gill and Marisol Sampedro Castaneda and Irene Matucci and Noreen Eder and Suzanne Claxton and Helen R. Flynn and Ambrosius P. Snijders and Roger George and Sila K. Ultanir},
  journal={Life Science Alliance},
Novel GAK phosphorylation targets are identified using chemical genetic methods. One of the substrates is the α subunit of the Na+/K+-ATPase, phosphorylation of which is necessary for its surface trafficking from endosomes. Conserved functions of NAK family kinases are described. Cyclin G–associated kinase (GAK) is a ubiquitous serine/threonine kinase that facilitates clathrin uncoating during vesicle trafficking. GAK phosphorylates a coat adaptor component, AP2M1, to help achieve this function… 

Figures and Tables from this paper

Measuring enzyme activities in crude homogenates: Na+/K+-ATPase as a case study in optimizing assays.

Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies

There is still much to investigate on this newly identified and converging pathway of vesicular dynamics and PD, which will aid in better understanding and suggest novel therapeutic strategies for PD patients.



FXYD Proteins: New Tissue-Specific Regulators of the Ubiquitous Na,K-ATPase

A novel regulatory mechanism was defined that is mediated by interaction of Na,K-ATPase with small proteins of the FXYD family, which possess a single transmembrane domain and so far have been considered as channels or regulators of ion channels.

Functional roles of Na,K-ATPase subunits

  • K. Geering
  • Biology
    Current opinion in nephrology and hypertension
  • 2008
A better understanding of the multiple functional roles of the accessory subunits of Na,K-ATPase is crucial to appraise their influence on physiological processes and their implication in pathophysiological states.

Na,K-ATPase subunit heterogeneity as a mechanism for tissue-specific ion regulation.

Identification of Novel ERK2 Substrates through Use of an Engineered Kinase and ATP Analogs*

This work engineered a mutant ERK2 in which a bulky amino acid residue in the ATP binding site is changed to glycine, allowing this mutant to utilize an analog of ATP that cannot be used by wild-type ERK1 or other cellular kinases, and identified the ubiquitin ligase EDD and the nucleoporin Tpr as two novel substrates of ERK 2.

Canonical interaction of cyclin G associated kinase with adaptor protein 1 regulates lysosomal enzyme sorting.

Interactions between the PsiG[PDE][PsiLM]-motif sequences in GAK and the AP1-gamma-ear domain are critical for the recruitment of GAK to the TGN and the function of G AK in lysosomal enzyme sorting.

Multiple Roles for Cyclin G‐Associated Kinase in Clathrin‐Mediated Sorting Events

It is demonstrated that GAK plays a role in the clathrin‐dependent trafficking from the trans Golgi network, and the specificity of GAK is very similar to that of adaptor‐associated kinase 1, another mammalian adaptor kinase.

Tissue-specific Expression of the Na,K-ATPase β3 Subunit

Structural features and tissue distribution of the β3 protein are described, utilizing an antiserum specific for its N terminus, and it is confirmed that β3 is a glycoprotein containing N-linked carbohydrate chains.

CK2 and GAK/auxilin2 Are Major Protein Kinases in Clathrin‐Coated Vesicles

It is shown that CK2 is responsible for the phosphorylation of the majority of CCV‐associated proteins that are subject to phosphorylated, and that the ‘stripped’ CCV membranes that remain once the peripheral membrane proteins have been removed from CCVs inhibit CK2 but not GAK/auxilin2 activity.

The Functional Role of β Subunits in Oligomeric P-Type ATPases

Increasing experimental evidence suggests that β assembly is a highly ordered, β isoform-specific process, which is mediated by multiple interaction sites that contribute in a coordinate, multistep process to the structural and functional maturation of Na,K- and H, K-ATPases.

Structure, expression, and chromosomal localization of human GAK.

The cloning of a cDNA encoding human GAK is reported and all of the unique motifs that characterize rat GAK, such as the presence of a Ser/Thr kinase domain, a tensin/auxilin homologous domain, and a Tyr phosphorylation target site, are conserved.