TRIM9-dependent ubiquitination of DCC constrains kinase signaling, exocytosis, and axon branching

نویسندگان

  • Melissa Plooster
  • Shalini Menon
  • Cortney C. Winkle
  • Fabio L. Urbina
  • Caroline Monkiewicz
  • Kristen D. Phend
  • Richard J. Weinberg
  • Stephanie L. Gupton
چکیده

Extracellular netrin-1 and its receptor deleted in colorectal cancer (DCC) promote axon branching in developing cortical neurons. Netrin-dependent morphogenesis is preceded by multimerization of DCC, activation of FAK and Src family kinases, and increases in exocytic vesicle fusion, yet how these occurrences are linked is unknown. Here we demonstrate that tripartite motif protein 9 (TRIM9)-dependent ubiquitination of DCC blocks the interaction with and phosphorylation of FAK. Upon netrin-1 stimulation TRIM9 promotes DCC multimerization, but TRIM9-dependent ubiquitination of DCC is reduced, which promotes an interaction with FAK and subsequent FAK activation. We found that inhibition of FAK activity blocks elevated frequencies of exocytosis in vitro and elevated axon branching in vitro and in vivo. Although FAK inhibition decreased soluble N-ethylmaleimide attachment protein receptor (SNARE)-mediated exocytosis, assembled SNARE complexes and vesicles adjacent to the plasma membrane increased, suggesting a novel role for FAK in the progression from assembled SNARE complexes to vesicle fusion in developing murine neurons.

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عنوان ژورنال:

دوره 28  شماره 

صفحات  -

تاریخ انتشار 2017