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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 46

Oculocerebrorenal syndrome of Lowe (OCRL) Skeletal muscle and kidney enriched inositol
Oculocerebrorenal syndrome of Lowe (OCRL) is a phosphatase (SKIP)
Rho-GAP-domain-containing enzyme that can hydro- As its name implies, skeletal muscle- and kidney-enriched
lyse both inositol phosphates (Ins1,4,5P 3 and Ins1,3,4,5P 4 ) inositol phosphatase (SKIP) is strongly expressed in
and the phosphoinositides PtdIns4,5P 2 and PtdIns3,4,5P 3 . skeletal muscle and kidney, but is also found in heart
OCRL also contains an ASH [ASPM (abnormal spindle- and brain. It’s C-terminal SKICH domain attaches it to
like microcephaly-associated protein/SPD2 (spindle pole the plasma membrane and to membranes in the perinuc-
body2)/hydin] domain, which is thought to provide a lear region. It acts to hydrolyse both PtdIns4,5P 2 and
binding site for microtubules. One of the functions of PtdIns3,4,5P 3 and has been implicated in insulin signalling.
OCRL is to control membrane and protein trafficking
during endocytosis where it operates primarily at the in- Sac3/Fig4
terface between the trans-Golgi network (TGN) and the The suppressor of actin 3 (Sac3), which is the mammalian
endosomes. orthologue of Fig4 in yeast, is a SAC domain lipid phos-
A deficiency of this enzyme is responsible for Lowe’s phatase that removes the 5-phosphate from PtdIns3,5P 2 to
oculocerebrorenal (OCRL) syndrome.Somepatientswith form PtdIns3P (see step 13 in Module 2: Figure phosphoin-
Dent’s disease also carry mutations in OCRL. ositide metabolism). Sac3/Fig4 is part of the PAS complex
and has an important structural role in that it also helps to
Synaptojanin facilitate the kinase activity of PIKfyve that operates in the
There are two synaptojanins: synaptojanin 1 (SJ1) and PtdIns3,5P 2 signalling cassette (Module 2: Figure PIKfyve
synaptojanin 2 (SJ2). activation).
Mutations in Sac3/Fig3 have been linked to
Synaptojanin 1 (SJ1) Charcot-Marie-Tooth disease 4J.
Synaptojanin 1 (SJ1) is a multi-functional inositol poly-
phosphate 5-phosphatase that has an important role in the Inositol phosphate metabolism
process of endocytosis (Module 4: Figure endocytosis). The Ca 2 + -mobilizing messenger function of inositol
There are two lipid phosphatase domains arranged in tan- 1,4,5-trisphosphate (InsP 3 ) is terminated through its meta-
dem: an N-terminal Sac1 domain, which dephosphorylates bolism by a complex inositol phosphate metabolic path-
PtdIns3P and PtdIns4P, and an adjacent 5-phosphatase that way (Module 2: Figure inositol phosphate metabolism)
acts on PtdIns4,5P 2 and PtdIns3,4,5P 3 . The C-terminal re- that has two main functions. Firstly, it produces free inos-
gion has a proline-rich domain (PRD) that targets synpto- itol that is resynthesized to PtdIns, which can be reused
janins to the SH3 domains of dynamin, endophilin and for further signalling. Secondly, it generates an assortment
amphiphysin on clathrin-coated pits (Module 4: Figure of inositol phosphates, some of which contribute to the
scission of endocytic vesicles). Alternative splicing of this multipurpose inositol polyphosphate signalling pathway.
region gives rise to the SJ1-145 and SJ1-170 isoforms. The The Ins1,4,5P 3 that enters the metabolic pathway is
former is strongly expressed in presynaptic terminals. SJ1 metabolized via two pathways. It is dephosphorylated by
has a primary role in coat removal in the final stages of en- Type I inositol polyphosphate 5-phosphatase (step 1) to
docytosis and is particularly important for synaptic vesicle form Ins1,4P 2 or it can be phosphorylated by InsP 3 3-
recycling. Since SJ1 is distributed throughout the neuron, kinase to form Ins1,3,4,5P 4 (step 4). Both Ins1,4P 2 and
it also plays a role in postsynaptic endocytosis. Ins1,3,4,5P 4 are putative messengers in the multipurpose
The activity of SJ1 is regulated by a phosphorylation/ inositol polyphosphate signalling pathway. The Ins1,4P 2
dephosphorylation cycle operated by the dual- is sequentially dephosphorylated to free inositol. The
specificity tyrosine-phosphorylation regulated kinase Ins1,3,4,5P 4 is dephosphorylated to Ins1,3,4P 3 , which oc-
1A (DYRK1A) and calcineurin (CaN) respectively. cupies an important position in the metabolic pathway
in that either it is dephosphorylated down to inositol,
Synaptojanin 2 (SJ2) as part of an inositol recycling pathway, or it can be
Synaptojanin 2 (SJ2) has a catalytic domain that closely phosphorylated further to form additional inositol poly-
resembles that of synaptojanin 1 (SJ1). Despite this close phosphates. The inositol phosphates in the pink boxes in
similarity, SJ2 does seem to have some distinct functions. Module 2: Figure inositol phosphate metabolism have been
Like SJ1, SJ2 has also been implicated in clathrin-mediated implicated as intracellular messengers. InsP 3 mobilizes in-
endocytosis. ternal Ca 2 + and the putative functions of the others are
described in the multipurpose inositol polyphosphate sig-
Proline-rich inositol polyphosphate 5-phosphatase nalling pathway.
(PIPP) Metabolism of the inositol phosphates is carried out by
The proline-rich inositol polyphosphate 5-phosphatase a large number of inositol phosphate kinases and phos-
(PIPP) has N- and C-terminal proline-rich domains. phatases (Module 2: Figure inositol phosphate metabol-
There also is a SKICH domain responsible for attaching ism):
PIPP to the plasma membrane where it acts to hydro-
lyse PtdIns4,5P 2 and PtdIns3,4,5P 3 . It can also hydrolyse Inositol polyphosphate 5-phosphatase (INPPs)
Ins1,4,5P 3 and Ins1,3,4,5P 4 . It is highly expressed in the This large family of enzymes, which are products of mul-
brain where it appears to function in neurite extension. tiple genes and splice variants, removes the 5-phosphate

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