4.6 Article

The tumor suppressor protein DLC1 maintains protein kinase D activity and Golgi secretory function

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 37, Pages 14407-14416

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.003787

Keywords

protein kinase D (PKD); Rho (Rho GTPase); deleted in liver cancer 1 (DLC1); secretion; kinetics; model selection; profile likelihood; trans-Golgi network; kinetic modeling

Funding

  1. Heisenberg program of the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)) [OL239/8]
  2. DFG within the Cluster of Excellence in Simulation Technology at the University of Stuttgart [EXC 310/2]

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Many newly synthesized cellular proteins pass through the Golgi complex from where secretory transport carriers sort them to the plasma membrane and the extracellular environment. The formation of these secretory carriers at the trans-Golgi network is promoted by the protein kinase D (PKD) family of serine/threonine kinases. Here, using mathematical modeling and experimental validation of the PKD activation and substrate phosphorylation kinetics, we reveal that the expression level of the PKD substrate deleted in liver cancer 1 (DLC1), a Rho GTPase-activating protein that is inhibited by PKD-mediated phosphorylation, determines PKD activity at the Golgi membranes. RNAi-mediated depletion of DLC1 reduced PKD activity in a Rho-Rho-associated protein kinase (ROCK)-dependent manner, impaired the exocytosis of the cargo protein horseradish peroxidase, and was associated with the accumulation of the small GTPase RAB6 on Golgi membranes, indicating a protein-trafficking defect. In summary, our findings reveal that DLC1 maintains basal activation of PKD at the Golgi and Golgi secretory activity, in part by down-regulating Rho-ROCK signaling. We propose that PKD senses cytoskeletal changes downstream of DLC1 to coordinate Rho signaling with Golgi secretory function.

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