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Function and dysfunction of the PI system in membrane trafficking.

Vicinanza M, D'Angelo G, Di Campli A, De Matteis MA - EMBO J. (2008)

Bottom Line: This important role of the PIs is mainly due to their versatile nature, which is in turn determined by their fast metabolic interconversions.PIs can be tightly regulated both spatially and temporally through the many PI kinases (PIKs) and phosphatases that are distributed throughout the different intracellular compartments.In spite of the enormous progress made in the past 20 years towards the definition of the molecular details of PI-protein interactions and of the regulatory mechanisms of the individual PIKs and phosphatases, important issues concerning the general principles of the organisation of the PI system and the coordination of the different PI-metabolising enzymes remain to be addressed.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.

ABSTRACT
The phosphoinositides (PIs) function as efficient and finely tuned switches that control the assembly-disassembly cycles of complex molecular machineries with key roles in membrane trafficking. This important role of the PIs is mainly due to their versatile nature, which is in turn determined by their fast metabolic interconversions. PIs can be tightly regulated both spatially and temporally through the many PI kinases (PIKs) and phosphatases that are distributed throughout the different intracellular compartments. In spite of the enormous progress made in the past 20 years towards the definition of the molecular details of PI-protein interactions and of the regulatory mechanisms of the individual PIKs and phosphatases, important issues concerning the general principles of the organisation of the PI system and the coordination of the different PI-metabolising enzymes remain to be addressed. The answers should come from applying a systems biology approach to the study of the PI system, through the integration of analyses of the protein interaction data of the PI enzymes and the PI targets with those of the 'phenomes' of the genetic diseases that involve these PI-metabolising enzymes.

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Related in: MedlinePlus

The PI kinases and phosphatases and their genetic defects. (A) Schematic representation of the PI metabolic cycle with the PIKs indicated in blue, and the PI phosphatases in green. (B) Listing of the different isoforms of the PIKs and PI phosphatases, together with their domain organisation and their corresponding genetic disease and knockout or knockdown phenotypes in mice. RSBD, regulatory subunit-binding domain; C2, conserved region 2; HD, helical domain; PRD, proline-rich domain, NLS, nuclear localisation signal; LKU, lipid kinase unique domain; PH, pleckstrin-homology domain; SRD, serine-rich domain; CRD, cysteine-rich domain; FYVE, Fab1 YOTB Vac1 EEA1; DEP, domain present in dishevelled, EGL-10 and pleckstrin; TCP1, tailless complex polypeptide-1; SPEC, spectrin repeat; PH-GRAM, pleckstrin homology glucosyltransferases, Rab-like GTPase activators and myotubularins; DENN, differentially expressed in normal versus neoplastic; LZ, leucine zipper; TM, transmembrane domain; ASH, abnormal spindle-like microcephaly-associated protein (ASPM), C. elegans centrosomal protein (SPD-2), hydrocephalus-associated protein (Hydin); RhoGAP, Rho-GTPase-activating protein; SAC, yeast suppressor of actin 1; Skitch, SKIP carboxyl homology domain; SH2, phosphotyrosine-binding module 2; SAM, sterile alpha-motif domain.
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f1: The PI kinases and phosphatases and their genetic defects. (A) Schematic representation of the PI metabolic cycle with the PIKs indicated in blue, and the PI phosphatases in green. (B) Listing of the different isoforms of the PIKs and PI phosphatases, together with their domain organisation and their corresponding genetic disease and knockout or knockdown phenotypes in mice. RSBD, regulatory subunit-binding domain; C2, conserved region 2; HD, helical domain; PRD, proline-rich domain, NLS, nuclear localisation signal; LKU, lipid kinase unique domain; PH, pleckstrin-homology domain; SRD, serine-rich domain; CRD, cysteine-rich domain; FYVE, Fab1 YOTB Vac1 EEA1; DEP, domain present in dishevelled, EGL-10 and pleckstrin; TCP1, tailless complex polypeptide-1; SPEC, spectrin repeat; PH-GRAM, pleckstrin homology glucosyltransferases, Rab-like GTPase activators and myotubularins; DENN, differentially expressed in normal versus neoplastic; LZ, leucine zipper; TM, transmembrane domain; ASH, abnormal spindle-like microcephaly-associated protein (ASPM), C. elegans centrosomal protein (SPD-2), hydrocephalus-associated protein (Hydin); RhoGAP, Rho-GTPase-activating protein; SAC, yeast suppressor of actin 1; Skitch, SKIP carboxyl homology domain; SH2, phosphotyrosine-binding module 2; SAM, sterile alpha-motif domain.

Mentions: The phosphoinositides (PIs) derive from reversible phosphorylation in three of the five hydroxyl groups of the inositol headgroup of the ‘parent' PI, phosphatidylinositol (PtdIns). This process operates through the large repertoire of PI kinases (PIKs) and PI phosphatases that are present in practically all cell compartments (Figures 1 and 2). The combined activities of the various isoforms of these PIKs and PI phosphatases provide a dynamic equilibrium between the seven distinct, but interconvertible, PI species (Figure 1). It is now clear that all of these different PIs are ‘active' in their own right, rather than many just serving as intermediates in the synthesis of the higher phosphorylated species.


Function and dysfunction of the PI system in membrane trafficking.

Vicinanza M, D'Angelo G, Di Campli A, De Matteis MA - EMBO J. (2008)

The PI kinases and phosphatases and their genetic defects. (A) Schematic representation of the PI metabolic cycle with the PIKs indicated in blue, and the PI phosphatases in green. (B) Listing of the different isoforms of the PIKs and PI phosphatases, together with their domain organisation and their corresponding genetic disease and knockout or knockdown phenotypes in mice. RSBD, regulatory subunit-binding domain; C2, conserved region 2; HD, helical domain; PRD, proline-rich domain, NLS, nuclear localisation signal; LKU, lipid kinase unique domain; PH, pleckstrin-homology domain; SRD, serine-rich domain; CRD, cysteine-rich domain; FYVE, Fab1 YOTB Vac1 EEA1; DEP, domain present in dishevelled, EGL-10 and pleckstrin; TCP1, tailless complex polypeptide-1; SPEC, spectrin repeat; PH-GRAM, pleckstrin homology glucosyltransferases, Rab-like GTPase activators and myotubularins; DENN, differentially expressed in normal versus neoplastic; LZ, leucine zipper; TM, transmembrane domain; ASH, abnormal spindle-like microcephaly-associated protein (ASPM), C. elegans centrosomal protein (SPD-2), hydrocephalus-associated protein (Hydin); RhoGAP, Rho-GTPase-activating protein; SAC, yeast suppressor of actin 1; Skitch, SKIP carboxyl homology domain; SH2, phosphotyrosine-binding module 2; SAM, sterile alpha-motif domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2536629&req=5

f1: The PI kinases and phosphatases and their genetic defects. (A) Schematic representation of the PI metabolic cycle with the PIKs indicated in blue, and the PI phosphatases in green. (B) Listing of the different isoforms of the PIKs and PI phosphatases, together with their domain organisation and their corresponding genetic disease and knockout or knockdown phenotypes in mice. RSBD, regulatory subunit-binding domain; C2, conserved region 2; HD, helical domain; PRD, proline-rich domain, NLS, nuclear localisation signal; LKU, lipid kinase unique domain; PH, pleckstrin-homology domain; SRD, serine-rich domain; CRD, cysteine-rich domain; FYVE, Fab1 YOTB Vac1 EEA1; DEP, domain present in dishevelled, EGL-10 and pleckstrin; TCP1, tailless complex polypeptide-1; SPEC, spectrin repeat; PH-GRAM, pleckstrin homology glucosyltransferases, Rab-like GTPase activators and myotubularins; DENN, differentially expressed in normal versus neoplastic; LZ, leucine zipper; TM, transmembrane domain; ASH, abnormal spindle-like microcephaly-associated protein (ASPM), C. elegans centrosomal protein (SPD-2), hydrocephalus-associated protein (Hydin); RhoGAP, Rho-GTPase-activating protein; SAC, yeast suppressor of actin 1; Skitch, SKIP carboxyl homology domain; SH2, phosphotyrosine-binding module 2; SAM, sterile alpha-motif domain.
Mentions: The phosphoinositides (PIs) derive from reversible phosphorylation in three of the five hydroxyl groups of the inositol headgroup of the ‘parent' PI, phosphatidylinositol (PtdIns). This process operates through the large repertoire of PI kinases (PIKs) and PI phosphatases that are present in practically all cell compartments (Figures 1 and 2). The combined activities of the various isoforms of these PIKs and PI phosphatases provide a dynamic equilibrium between the seven distinct, but interconvertible, PI species (Figure 1). It is now clear that all of these different PIs are ‘active' in their own right, rather than many just serving as intermediates in the synthesis of the higher phosphorylated species.

Bottom Line: This important role of the PIs is mainly due to their versatile nature, which is in turn determined by their fast metabolic interconversions.PIs can be tightly regulated both spatially and temporally through the many PI kinases (PIKs) and phosphatases that are distributed throughout the different intracellular compartments.In spite of the enormous progress made in the past 20 years towards the definition of the molecular details of PI-protein interactions and of the regulatory mechanisms of the individual PIKs and phosphatases, important issues concerning the general principles of the organisation of the PI system and the coordination of the different PI-metabolising enzymes remain to be addressed.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.

ABSTRACT
The phosphoinositides (PIs) function as efficient and finely tuned switches that control the assembly-disassembly cycles of complex molecular machineries with key roles in membrane trafficking. This important role of the PIs is mainly due to their versatile nature, which is in turn determined by their fast metabolic interconversions. PIs can be tightly regulated both spatially and temporally through the many PI kinases (PIKs) and phosphatases that are distributed throughout the different intracellular compartments. In spite of the enormous progress made in the past 20 years towards the definition of the molecular details of PI-protein interactions and of the regulatory mechanisms of the individual PIKs and phosphatases, important issues concerning the general principles of the organisation of the PI system and the coordination of the different PI-metabolising enzymes remain to be addressed. The answers should come from applying a systems biology approach to the study of the PI system, through the integration of analyses of the protein interaction data of the PI enzymes and the PI targets with those of the 'phenomes' of the genetic diseases that involve these PI-metabolising enzymes.

Show MeSH
Related in: MedlinePlus