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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 45

Inositol lipid phosphatases in the active site to form a disulphide bond with Cys-71.
There are a large number of inositol lipid phosphatases that This disulphide bond formation is specifically reversed by
contribute to inositol lipid metabolism (Module 2: Figure thioredoxin. A reversible inactivation of PTEN may thus
phosphoinositide metabolism). The situation is complic- contribute to the accumulation of PtdIns3,4,5P 3 (Module
ated in that some of these phosphatases have a broad range 2: Figure plasma membrane ROS formation), which may
of substrates and can act on both inositol lipids and inos- thus help to promote proliferation by switching off the
itol phosphates. The following are the phosphatases that metabolism of the 3-phosphorylated lipid second mes-
act predominantly on inositol lipids: sengers. This reversible inactivation of PTEN contrib-
utes to the accumulation of PtdIns3,4,5P 3 by setting
• Phosphatase and tensin homologue deleted on chromo- up a positive-feedback loop, since the formation of this
some 10 (PTEN) lipid messenger is responsible for stimulating the produc-
• 5-Phosphatase II tion of H 2 O 2 (Module 2: Figure plasma membrane ROS
• Inositol polyphosphate 5E-phosphatase (INPP5E) formation).
• Myotubularins There are additional enzymes that hydrolyse the 3-
• Oculocerebrorenal syndrome of Lowe (OCRL) phosphorylated position. Transmembrane phosphatase
• Proline-rich inositol polyphosphate 5-phosphatase with tensin homology (TPTE) is localized to the plasma
(PIPP) membrane, but appears not to have phosphatase activity.
• Skeletal muscle and kidney enriched inositol phos- TPTE and PTEN homologous inositol lipid phosphatase
phatase (SKIP) (TPIP) occurs as α and β isoforms. The TPIPα isoform
• Synaptojanins hydrolyses PtdIns3,4,5P 3 , PtdIns3,5P 2 , PtdIns3,4P 2 and
PtdIns3P. It has N-terminal transmembrane domains that
5-Phosphatase II appear to localize the protein to the ER.
5-Phosphatase II, which is also known as inositol PTEN is a potent tumour suppressor that is frequently
polyphosphate 5B-phosphatase (INPP5B), is a 75 kDa inactivated in many different cancers, e.g. endometrial,
protein that preferentially hydrolyses PtdIns4,5P 2 and prostate, mammary carcinomas, melanomas and thyroid
PtdIns3,4,5P 3 , but can also act on the inositol phosphates tumours. When PTEN is inactivated in neurons, there is a
Ins1,4,5P 3 and Ins1,3,4,5P 4 . This 5-phosphatase II closely progressive increase in cell size and increased phosphoryla-
resembles oculocerebrorenal syndrome of Lowe (OCRL) tion of protein kinase B (PKB) that create cerebellar ab-
both in structure and function. Like OCRL, it has a cent- normalities resembling those seen in human Lhermitte--
ral 5-phosphatase catalytic domain followed by an ASH Duclos disease (LDD).
domain and a RhoGAP domain. The ASH domain enables Germline mutations in the PTEN gene have been im-
it to interact with Rab5. The C-terminal end has a CAAX plicated in the development of Cowden’s disease and
region that can be prenylated to facilitate its membrane Bannayan--Zonana syndrome, where there is an increased
localization. risk of breast and thyroid cancers. An increase in the ex-
5-Phosphatase II is located on the Golgi where it may pression of PTEN by the tumour suppressor p53 may
function in the trafficking of vesicles to both the ER and contribute to p53-induced apoptosis.
to the early endosome.
Myotubularins
Inositol polyphosphate 5E-phosphatase (INPP5E)
There is a large family of myotubularins that function as
Inositol polyphosphate 5E-phosphatase (INPP5E), which
lipid phosphatases that dephosphorylate PtdIns3P and also
is also known as Type IV 5-phosphatase, is widely ex- PtdIns3,5P 2 (Module 2: Figure phosphoinositide meta-
pressed where it functions to remove the 5-phosphate from bolism). They may also act on PtdIns3,5P 2 . Mammalian
PtdIns4,5P 2 , PtdIns3,5P 2 and PtdIns3,4,5P 3 .
cells express 15 myotubularins. The founding member is
MTM1 and the remainder are MTMR2--MTMR14. These
Phosphatase and tensin homologue deleted on enzymes have a phosphatase domain, and a GRAM do-
chromosome 10 (PTEN) main, which associates with membranes and a C-terminal
PTEN (phosphatase and tensin homologue deleted on coiled-coil domain that links these enzymes to other pro-
chromosome 10) is a lipid phosphatase that is mutated teins. One of the isoforms, MTMR6, appears to have a
in many human cancers. Its gene is a tumour suppressor, specific role in the PtdIns3P signalling cassette. Hydro-
which functions in cell migration, proliferation and sur- lysis of PtdIns3P may control the activity of the Ca 2 + -
vival. PTEN inactivates the 3-phosphorylated lipid second activated intermediate-conductance (IK) channel (K Ca 3.1),
messengers that operate within the PtdIns 3-kinase sig- and this may be of particular significance for the relation-
nalling cassette. It functions to remove the phosphate from ship between K + channels and cell proliferation.
the 3-position of PtdIns3,4P 2 and PtdIns3,4,5P 3 (Module These enzymes are of interest because mutations
2: Figure phosphoinositide metabolism). in MTM1 are responsible for X-linked recessive
PTEN is a redox-sensitive enzyme, which may contrib- myotubular myopathy and MTMR2 is mutated in
ute to a positive-feedback loop that enhances redox sig- Charcot-Marie-Tooth disease 4B. Missense mutations in
nalling (Module 2: Figure plasma membrane ROS form- MTMR14 have also been described in centronuclear my-
ation). It is inhibited by H 2 O 2 , which induces Cys-124 opathy (CNM).

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