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Zuzana Kadlecova

Integration of NAK kinases with membrane trafficking machinery

Despite the critical role that endocytosis plays in health and disease, surprisingly little is known about how it is regulated through post-translational modification of its components. Phosphorylation/dephosphorylation events could finely tune the locations of endocytic accessory proteins, their activities and cargo specificities to maintain cellular fitness under conditions of stress. However, it is poorly understood which kinases and phosphatases influence endocytosis, despite their potential as therapeutic targets in a number of diseases. We are a cell biology laboratory interested in gaining a better understanding of the molecular regulation of endocytosis and its integration within wider cell signaling and metabolic homeostasis.

Recently, our collaborative efforts identified the molecular basis of the NAK kinase-mediated phosphorylation of the most abundant clathrin adaptor, AP2 (link to paper). We showed that AP2 phosphorylation not only leads to changes in its interactome, but is a major decision point in clathrin-mediated endocytosis, capable of affecting its rates.

We are building on these findings by exploring systematically and mechanistically how kinases and phosphatases regulate clathrin-mediated endocytosis. We focus on NAK kinases, which are also recent drug development targets for neuropathic pain, and were linked by GWAS to an increased neurodegeneration risk.

Recent key publications

1. Wrobel AG*, Kadlecova Z*^#, Kamenicky J, Yang JC, Herrmann T, Kelly BT, McCoy A, Evans P, Martin S, Müller S, Sroubek F, Neuhaus D, Höning S^, Owen DJ, (2019). Temporal ordering in endocytic clathrin-coated vesicle formation via AP2 phosphorylation. Developmental Cell 50, 4, 494-508.e11.
*Equal contribution, #Lead author, ^Corresponding authors.

2. Kadlecova Z, Spielman SJ, Loerke D, Mohanakrishnan A, Reed DK, Schmid SL, (2017).    Regulation of clathrin-mediated endocytosis by hierarchical allosteric activation of AP2. Journal of Cell Biology. 2, 216,1,167-179.

3. Lakoduk AM, Kadlecova Z, Schmid SL, (2020).  A functionally neutral single chain antibody to measure beta‐1 integrin uptake and recycling. Traffic 21:590–602.

4. Zaritsky A, Obolski U, Gan Z, Reis CR, Kadlecova Z, Du Y, Schmid SL, Danuser G, (2017). Decoupling global biases and local interactions between cell biological variables. eLife. 13, 6.

 

 

 

 

 

 

 

 

 

 

 

Sir Henry Dale Fellow
(from January 1st 2021)

Department: Clinical Biochemistry

email: zk241@cam.ac.uk

 

Plain English

All living cells are surrounded by cell membranes. These are essential to keep the inside of the cell separate from its outside surroundings, but are also very dynamic, controlled structures to make sure that the cell remains healthy and functioning within its environment. Problems with the functioning of cell membranes can result in disease. It is therefore important to understand the complex processes which control cell membrane structure and function, and one of them is a process called endocytosis.

Endocytosis is a process in which cells use plasma membrane to package and transport essential materials such as nutrients, from outside to inside. By turning-over the cell membrane, endocytosis is also a key mechanism for controlling the protein content of the plasma membrane and its interactions with neighbouring cells.

In in the lab we are using powerful microscopes and biochemical techniques to study the proteins which control endocytosis, and how the process might go wrong in disease. 

Funding

The Royal Society and Wellcome Trust

Group Members

I am recruiting!