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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 96

Module 2: Figure PLD isoforms

Palmitate Palmitate
(Cys 240) (Cys 241)
HKD HKD
PLD1 PX PH I II III IV 1072

Palmitate Palmitate
(Cys 240) (Cys 241)
HKD HKD
PLD2 PX PH I II III IV 1034

The domain structure of phospholipase D (PLD).
The two isoforms of phospholipase D (PLD) have similar domain structures. Palmitoylation of Cys-240 and Cys-241 within the pleckstrin homology (PH)
domain play a critical role in localizing the enzyme to membranes. There are four conserved sequences (I--IV). Domains II and IV contain HXKXXXXD,
the so-called HKD motif, which come together to form the catalytic domain. The C-terminal region has a phox homology (PX) domain and a PH
domain responsible for the binding of PtdIns4,5P 2 during activation of the enzyme (Module 2: Figure PLD signalling).

Module 2: Figure PLD signalling

Growth Chemotactic
factors Antigen Chemokines factors
LPA

PIP PLC DAG PLC PIP
2 2
PI3K
PKC
Ras LPA
PIP Ral-GDS
3 PA
hydrolase PLA2
Protein phosphatase 1
Arf Rho RalA
Sphingosine kinase
PA +
mTOR
Membrane budding and fusion
PIP PtdIns4P-5K PIP 2 PLD1 PC
Plasma membrane OR
Endosomal membranes Membrane trafficking
Cytoskeletal organization
Inflammation
Phagocytosis
Proliferation
+ Secretion (Mast cells)
Respiratory burst

The phospholipase D (PLD) signalling pathway.
This signalling pathway depends upon the enzyme phospholipase D1 (PLD1), which associates primarily with intracellular membranes (e.g. Golgi and
endosomes), but is also found in the plasma membrane. The activation of PLD1 is linked to many receptors through a number of mechanisms that may
vary depending on the location and which of its many functions PLD is carrying out. One activator is protein kinase Cα (PKCα), through a mechanism
that is independent of its catalytic activity. Other major regulators are various small G proteins. Arf and Rho may be activated by the lipid messenger
PtdIns3,4,5-trisphosphate (PIP 3 ) formed by the PtdIns 3-kinase signalling cassette, whereas Ral A may be activated via Ras and the GTP/GDP
exchange factor Ral-GDS. In addition, PLD1 has an absolute requirement for PtdIns4,5P 2 (PIP 2 ), which may be part of a positive-feedback loop
because the PtdIns4P 5-kinase (PtdIns4P-5K) is activated by phosphatidic acid (PA). The action of PA is terminated either by a PA phosphohydrolase,
which removes phosphate to leave behind diacylglycerol (DAG), or by a phospholipase A 2 (PLA 2 ) to produce lysophosphatidic acid (LPA).

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