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Cell Signalling Biology Michael J. Berridge  Module 2  Cell Signalling Pathways                2  47




             Module 2: Figure phosphoinositide signalling systems



                                                          The PtdIns4,5P 2    The PtdIns 3-kinase
                                                          signalling cassette  signalling cassette




                           PtdIns           PtdIns4P       PtdIns4,5P 2        PtdIns3,4,5P 3




                              Inositol phosphate        InsP            DAG
                                metabolism                  3




                             The multipurpose                     The diacylglycerol (DAG)/
                             inositol polyphosphate                  protein kinase C
                             signalling cassette                    signalling cassette


                                                    The InsP / Ca 2+
                                                          3
                                                   signalling cassette



             PtdIns metabolism spawns a variety of signalling cassettes.
             The metabolism of PtdIns creates a number of lipid and inositol phosphate derivatives that operate a variety of signalling cassettes. PtdIns4,5P 2 is a
             nodal point for a number of signalling cassettes. It is the precursor that is hydrolysed to generate the second messengers inositol 1,4,5-trisphosphate
             (InsP 3 ) and diacylglycerol (DAG). It is phosphorylated further to form the lipid second messenger PtdIns3,4,5P 3 . The localized turnover of PtdIns4,5P 2
             also has a signalling role within the PtdIns4,5P 2 signalling cassette that regulates a variety of processes such as the cytoskeleton, control of the
             processes of membrane trafficking and exocytosis and the regulation of ion channels and exchangers. Finally, the InsP 3 enters a complex pathway
             of inositol phosphate metabolism that generates components of the multipurpose inositol polyphosphate signalling cassette.


             group from inositol lipids and, in some cases, can also act  allowing the enzyme to disperse into the cytosol, InsP 3
             on inositol phosphates. All members of the family share a  metabolism is severely curtailed. It seems that much of the
             central conserved catalytic domain:              InsP 3 is metabolized close to its site of action at the plasma
                                                              membrane.
             • 5-Phosphatase I                                Src homology 2 (SH2) domain-containing inositol
             • 5-Phosphatase II                               phosphatases (SHIP)
             • Oculocerebrorenal syndrome of Lowe (OCRL)      The Src homology 2 (SH2) domain-containing inositol
             • Src homology 2 (SH2) domain-containing inositol
                                                              phosphatases (SHIP1 and SHIP2) hydrolyse Ins1,3,4,5P 4
               phosphatase (SHIP)
                                                              and PtdIns3,4,5P 3 . The SHIPs, which come in different
             • Proline-rich inositol polyphosphate 5-phosphatase
                                                              forms, are found in haematopoietic cells, where they play
               (PIPP)
                                                              a role in inhibiting signalling. In B cells, for example, the
             • Skeletal muscle and kidney enriched inositol phos-
                                                              FcγRIIB receptor has an immunoreceptor tyrosine-based
               phatase (SKIP)
                                                              inhibitory motif (ITIM) to which SHIPs attach causing a
             • Synaptojanins
                                                              reduction in Ca 2 +  signalling by hydrolysing PtdIns3,4,5P 3
                                                              and thereby reducing the stimulatory effect of the Tec tyr-
             5-Phosphatase I
                                                              osine kinase family on phospholipase Cγ (Module 2: Fig-
             The 5-phosphatase I functions to hydrolyse the inos-
                                                              ure ROS effects on Ca 2 +  signalling). SHIPs perform a
             itol phosphates Ins1,4,5P 3 and Ins1,3,4,5P 4 (Steps 1 in
                                                              similar function in mast cells (Module 11: Figure mast cell
             Figure 2 inositol phosphate metabolism). If this enzyme
                                                              inhibitory signalling). SHIP1 functions to localize PIP 3 at
             is deleted, there is an increase in the level of InsP 3 ,  the front of the cell during neutrophil chemotaxis (Module
             and this was associated with a transformed phenotype.  11: Figure neutrophil chemotaxis).
             This enzyme is inhibited following phosphorylation by
             Ca 2 + /calmodulin-dependent protein kinase II (CaMKII).  Inositol polyphosphate 1-phosphatase
             Type I, which hydrolyses the inositol phosphates, is direc-  Steps 2 in Module 2: Figure inositol phosphate meta-
             ted to the membrane by isoprenylation of the C-terminal  bolism. This enzyme dephosphorylates both Ins1,3,4P 3
             region. If these membrane attachment sites are removed,  and Ins1,4P 2 . This enzyme has been implicated in the


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