Page 42 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 42

Module 2: Table continued
Substrate Product Comments
Synaptojanin 1 (SJ1) PtdIns4,5P 2 PtdIns4P Step 8 in Module 2: Figure
phosphoinositide metabolism.
Synaptojanin 1 (SJ1) PtdIns4,5P 2 PtdIns4P Removes protein coates following
scission of endocytic vesicles
(Module 4: Figure scission of
endocytic vesicles)
Oculocerebrorenal syndrome of Lowe PtdIns4,5P 2 PtdIns4P Mutations of OCRL cause Lowe’s
(OCRL) syndrome
PtdIns3,4,5P 3 PtdIns3,4P 2
Sac3 PtdIns3,5P 2 PtdIns3P Mammalian homologue of yeast Fig4 is
part of the PAS complex (Module 2:
PIKfyve activation)

1. The Class III PtdIns 3-kinase (PtdIns 3-K) adds the 5-position of PtdIns3,4P 2 by the PtdIns4P 5-k-
a phosphate to the 3-position of PtdIns to form inase (PtdIns4P 5-K) (i.e. the same enzyme used for
PtdIns3P. Step 8).
2. PtdIns 4-kinase (PtdIns 4-K) adds a phosphate to 11. The myotubularins remove the 3-phosphate from
the 4-position of PtdIns to form PtdIns4P. It can PtdIns3P and also from PtdIns3,5P 2 .
also be formed by removal of the 3-phosphate from 12. The 5-phosphate on PtdIns4,5P 2 is removed by vari-
PtdIns3,4P 2 by phosphatase and tensin homologue ous lipid phosphatases such as oculocerebrorenal syn-
deleted on chromosome 10 (PTEN). drome of Lowe (OCRL) and the synaptojanins.
3. The PIKfyve kinase is thought to be responsible for 13. The 5-phosphate on PtdIns3,5P 2 is removedbythe
adding a phosphate to the 5-position of PtdIns to form Sac domain phosphatase Sac3, which is an orthologue
PtdIns5P. of yeast Fig 4.
4. The PIKfyve also adds a phosphate to the 5-position
of PtdIns3P to form PtdIns3,5P 2 .The formationof Inositol lipid kinases
PtdIns3,5P 2 , which changes in cells following osmotic There are a number of inositol lipid kinases that function
stress, is a key component of the PtdIns3,5P 2 sig- to phosphorylate hydroxyls on the inositol headgroup of
nalling cassette (Module 2: Figure PIKfyve activation).
5. Types I and II PtdIns 3-kinase (PtdIns 3-K) add phosphatidylinositol.
a phosphate to the 3-position of PtdIns4P to form
PtdIns3,4P 2 . PtdIns3,4P 2 has been suggested to func- PtdIns 3-kinase (PtdIns 3-K)
tion as a messenger operating within the plasma mem- The PtdIns 3-kinases (PtdIns 3-Ks) are a family of en-
brane, where it serves to recruit and activate protein zymes that have been classified into three classes (Module
2: Figure PI 3-K family).
kinases such as protein kinase B (PKB). PtdIns3,4P 2
can also be formed by other enzymes (see Steps 6 and
7). Class I PtdIns 3-kinases
6. PtdInsP kinase II adds a phosphate to the 4-position The primary function of the Class I PtdIns 3-kinases is to
of PtdIns3P to form PtdIns3,4P 2 . The same enzyme phosphorylate PtdIns4,5P 2 to form the lipid second mes-
can add a phosphate to the 4-position of PtdIns5P to senger PtdIns3,4,5P 3 (Module 2: Figure PtdIns 3-kinase
form PtdIns4,5P 2 . signalling). These Class I enzymes are divided into two
7. Inositol polyphosphate 5-phosphatase such as Src ho- groups: five regulatory subunits and three catalytic sub-
mology 2 (SH2) domain-containing inositol phos- units (Module 2: Figure PI 3-K family).
phatase (SHIP) removes a phosphate from the 5- The Class IA enzymes are heterodimers that are formed
position of PtdIns 3,4,5P 3 to form PtdIns3,4P 2 . from a regulatory subunit combining with a catalytic sub-
8. A PtdIns4P 5-kinase (PtdIns4P 5-K) adds a phosphate unit. There are five regulatory subunits (p85α,p85β,p55α,
to the 5-position of PtdIns4P to form PtdIns4,5P 2 . p50α and p55γ), which are typical adaptor proteins. The
The latter can also be formed by Steps 6 and 9. p85 regulatory subunit contains an Src homology 3 (SH3)
PtdIns4P5-K can also phosphorylate PtdIns3,4P 2 to domain, a breakpoint-cluster-region homology (BH) do-
form PtdIns3,4,5P 3 . main, two proline-rich regions (P) on either side of the
9. Phosphatase and tensin homologue deleted on chro- BH domain and two Src homology (SH2) domains that
mosome 10 (PTEN) removes a phosphate from the are separated by a p110-binding domain, enabling them to
3-position of PtdIns3,4,5P 3 . interact with a p85-binding domain located on the three
10. A Class I PtdIns 3-kinase adds a phosphate to the catalytic subunits (p110α, p110β and p110δ). The differ-
3-position of PtdIns4,5P 2 to form PtdIns3,4,5P 3 . ent binding domains on the regulatory subunits enhance
PtdIns3,4,5P 3 , which functions as one of the second the versatility of the Class IA enzyme by enabling the
messengers in the PtdIns 3-kinase signalling pathway, catalytic subunit to be activated by interacting with a vari-
can also be formed by the addition of a phosphate to ety of signalling molecules:

C 2012 Portland Press Limited www.cellsignallingbiology.org