<p>A constitutively active mutant of the receptor protein tyrosine kinase KIT is a major cause of gastrointestinal stromal tumours (GISTs). Recently, we discovered that, during biosynthetic transport, the KIT mutant (KIT^mut) is retained in the Golgi/<i>trans-</i>Golgi network (TGN), where it activates downstream molecules. This retention is dependent on the phospholipase Cγ2–protein kinase D2–PI4 kinase IIIβ (PLCγ2–PKD2–PI4KIIIβ) pathway, which KIT^mut activates at the Golgi/TGN. The activated cascade aberrantly recruits GGA1 and the γ-adaptin subunit of AP1, resulting in KIT^mut retention in the Golgi/TGN. However, the precise mechanisms, including the mediators and effectors of the pathway, remain unclear. In humans, the phosphatidic acid-generating enzymes, phospholipase D1 (PLD1) and PLD2 are known downstream proteins of PKD. In the presence of the PLD inhibitor CAY10594, KIT^mut is released from the Golgi/TGN and subsequently degraded in lysosomes, leading to signal inactivation. Knockdown experiments indicated that PLD2 plays a role in KIT^mut retention. KIT^mut activates PLD2 through PKD2, but not PI4KIIIβ, for Golgi/TGN retention. PLD activity is required for the association of γ-adaptin with GGA1. Therefore, the KIT–PLCγ2–PKD2 pathway separately activates PLD2 and PI4KIIIβ to recruit γ-adaptin and GGA1. Collectively, these results suggest that KIT^mut retention is dependent on the activation of the PLCγ2–PKD2–PLD2 cascade in GIST cells.</p>