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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 64

Module 2: Figure PIKfyve activation

ArPIKfyve

PIKfyve

Sac3/Fig4
C Kinase Phosphatase
N FYVE
PtdIns3P PtdIns3,5P 2 PtdIns3P

PIKfyve-ArPIKfyve-Sac3 (PAS) core complex
The PIKfyve inositol lipid kinase, which phosphorylates PtdIns3P to PtdIns3,5P 2 , functions within a PAS complex containing the scaffolding protein
ArPIKfyve and the Sac3/Fig4 phosphatase. The latter hydrolyses PtdIns3,5P 2 back to PtdIns3P. Information for this drawing was taken from Figure 6
in Ikonomov et al. 2009.

(PAS) complex (Module 2: Figure PIKfyve activation). The • Early endosome sorting and intraluminal vesicle form-
N-terminal FYVE domain binds to the substrate PtdIns3P. ation (Module 4: Figure intraluminal endosomal vesicle
The Cpn160_TCP1 domain interacts with the associated formation)
regulator of PIKfyve (ArPIKfyve), which forms a dimer • Early endosome to plasma membrane trafficking
and functions as a scaffolding protein to assemble the PAS (Module 4: Figure early endosome budding)
complex. The C-terminal kinase domain is then positioned • Early endosome to trans-Golgi network (TGN) traf-
to catalyse the conversion of PtdIns3P into PtdIns3,5P 2 . ficking (Module 4: Figure endosome budding to TGN)
The suppressor of actin 3 (Sac3), which is the mammalian • Phagosome maturation (Module 4: Figure phagosome
orthologue of Fig4 in yeast, is a SAC domain lipid phos- maturation).
phatase that removes the 5-phosphate from PtdIns3,5P 2 to • Formation of PtdIns3P has a role to play in activating
form PtdIns3P. Sac3 is part of the PAS complex and has an the isolation membrane responsible for initiating the
important structural role in that it also helps to facilitate events of autophagy (Module 11: Figure autophagy).
the kinase activity of PIKfyve. • PtdIns3P plays a role in regulating the activity of the
Mutations in Sac3/Fig3 have been linked to intermediate conductance (IK) channel, particularly as
Charcot-Marie-Tooth disease 4J. part of the relationship between K + channels and cell
proliferation.

PtdIns3P signalling cassette PtdIns3P levels can be reduced through the action of
PtdIns3P, which is formed by the phosphorylation of the myotubularin family of 3-phosphatases (MTM1 and
PtdIns by the Class III PtdIns 3-kinase, has a specific role MTMR1--MTMR14). These enzymes are of interest be-
to play in controlling a number of cellular processes. cause MTM1 mutations are responsible for X-linked re-
One of the main functions of PtdIns3P is to regulate cessive myotubular myopathy, MTMR2 mutations occur
intracellular vesicle trafficking especially at the level of in Charcot-Marie-Tooth disease 4B and MTMR14 muta-
the early endosome (Module 2: Figure localized inositol tions have been linked to centronuclear myopathy (CNM).
lipid signalling). Most of the PtdIns3P is found on internal
membranes and particularly those that function in vesicle PtdIns4P signalling cassette
trafficking:
For a long time, PtdIns4P was considered to be only a
precursor of PtdIns4,5P 2 , but now there are indications
• This function is particularly evident in the endosome that it might have a signalling role to regulate membrane
vesicle fusion to the early endosome (Module 4: Figure and protein trafficking. One role is to control coat re-
endosome vesicle fusion) moval following the formation of clathrin-coated vesicles

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