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J. Biol. Chem., Vol. 277, Issue 39, 36280-36287, September 27, 2002

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Mixed Lineage Kinase 2 Interacts with Clathrin and Influences Clathrin-coated Vesicle Trafficking^*

Shiva Akbarzadeh, Hong Ji^§, David Frecklington^§, Nelly Marmy-Conus, Yee-Foong Mok, Leanne Bowes, Lisa Devereux, Martha Linsenmeyer, Richard J. Simpson^§, and Donna S. Dorow^¶

From the  Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne 8006, Victoria and ^§ Joint Proteomics Laboratory, Ludwig Institute for Cancer Research and Walter and Eliza Hall Institute of Medical Research, Parkville 3042, Victoria, Australia

Mixed lineage kinase 2 (MLK2) is a protein kinase that signals in the stress-activated Jun N-terminal kinase signal transduction pathway. We used immunoprecipitation and mass spectrometric analysis to identify MLK2-binding proteins in cell lines with inducible expression of green fluorescent protein-tagged MLK2. Here we report the identification of clathrin as a binding partner for MLK2 in both cultured cells and mammalian brain. We demonstrate that clathrin binding requires a motif (LLDMD) located near the MLK2 C terminus, which is similar to "clathrin box" motifs important for binding of clathrin coat assembly and accessory proteins to the clathrin heavy chain. A C-terminal fragment of MLK2 containing this motif binds strongly to clathrin, and mutation of the LLDMD sequence to LAAAD completely abrogates clathrin binding. We isolated clathrin-coated vesicles from green fluorescent protein-MLK2-expressing cells and from mouse brain lysates and found that MLK2 is enriched along with clathrin in these vesicles. In addition, we demonstrated that endogenous MLK2 co-immunoprecipitates with clathrin heavy chain from the vesicle-enriched fraction of mouse brain lysate. Furthermore, overexpression of MLK2 in cultured cells inhibits accumulation of labeled transferrin in recycling endosomes during receptor-mediated endocytosis. These findings suggest a role for MLK2 and the stress-signaling pathway at sites of clathrin activity in vesicle formation or trafficking.

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