Lipid activation of protein kinases

Lipids acutely control the amplitude, duration, and subcellular location of signaling by lipid second messenger-responsive kinases. Typically, this activation is controlled by membrane-targeting modules that allosterically control the function of kinase domains within the same polypeptide. Protein kinase C (PKC) has served as the archetypal lipid-regulated kinase, providing a prototype for lipid-controlled kinase activation that is followed by kinases throughout the kinome, including its close cousin, Akt (protein kinase B). This review addresses the molecular mechanisms by which PKC and Akt transduce signals propagated by the two major lipid second messenger pathways in cells, those of diacylglycerol signaling and phosphatidylinositol-3,4,5-trisphosphate (PIP3) signaling, respectively. Lipids acutely control the amplitude, duration, and subcellular location of signaling by lipid second messenger-responsive kinases. Typically, this activation is controlled by membrane-targeting modules that allosterically control the function of kinase domains within the same polypeptide. Protein kinase C (PKC) has served as the archetypal lipid-regulated kinase, providing a prototype for lipid-controlled kinase activation that is followed by kinases throughout the kinome, including its close cousin, Akt (protein kinase B). This review addresses the molecular mechanisms by which PKC and Akt transduce signals propagated by the two major lipid second messenger pathways in cells, those of diacylglycerol signaling and phosphatidylinositol-3,4,5-trisphosphate (PIP3) signaling, respectively. Cellular membranes form a platform of intense signaling activity. Serving as the site where extracellular signals are first received by the cell, they not only recruit and activate effector molecules, but they also provide a spring board to launch activated effector molecules throughout the cell. Protein kinases comprise one of the most common classes of effector molecules that transduce signals emanating from the plasma membrane. These kinases can be embedded in the plasma membrane, exemplified by the tyrosine kinase growth factor receptors, or can be either soluble or amphipathic membrane proteins that translocate on and off cellular membranes in response to appropriate signals. Soluble proteins are recruited to membranes by protein scaffolds, but there exists a class of amphipathic membrane kinases whose members directly bind lipid second messengers via specific membrane-targeting modules. It is this latter class of lipid-controlled kinases that forms the focus of this review.Despite the enormity of the kinome, few kinases (approximately 10%) directly bind and transduce lipid second messenger signals. Yet they transduce signals in two of the most pivotal signaling pathways in cells, notably the diacylglycerol and phosphatidylinositol 3 kinase pathways. To this end, lipid second messenger-regulated protein kinases contain modules that bind with high specificity and affinity to the relevant lipid second messengers (1Hurley J.H. Membrane binding domains.Biochim. Biophys. Acta. 2006; 1761: 805-811Crossref Membrane by the is the diacylglycerol J.H. and function of protein kinase C and the or modules as the J.H. phosphatidylinositol domains as the can in membrane of the kinase by with specific in by a J.H. by membrane Protein kinase two lipid second messenger-regulated kinases contain one or membrane-targeting modules whose membrane in protein kinase by the of of the major lipid second protein kinases. the of protein kinase which to the kinase of the kinome, kinases are members of the (protein kinases and of the kinome, where they for of the members of this the protein kinase C (PKC) of which there are and Protein kinase C and lipid signaling for cellular and of protein kinase and PKC contain domains and transduce signals that diacylglycerol Protein kinase also a and in the of and PKC 2006; of this in PKC and in not bind diacylglycerol J.H. and function of protein kinase C they the affinity of domains for the and domains of protein kinase C are membrane with specificity for by the kinases in this contain domains that members of the Akt of kinases contain a that phosphatidylinositol-3,4,5-trisphosphate as one of the major mechanisms to transduce signals that activate phosphatidylinositol 3 kinase is also in one of the protein kinase of in and Biophys. Acta. the kinase for most of the kinases in also has a with high this kinase is in cells, with signaling kinase of in and Biophys. Acta. the of kinase domains bind a is in the kinase, as a and and of protein is the most to by protein but that kinases as a the affinity of the for to where this lipid and protein on a 2006; kinases a the Protein kinase two and the in and Protein the of PKC this in a the of PKC and protein kinase the not to function as a It is that for of the major modules the and there that not bind as exemplified by the in and protein kinase the domains in PKC and and the in common in the of amphipathic membrane kinases that translocate on and off membranes is the of two membrane-targeting domains Protein kinase a for of protein function by two membrane-targeting Biophys. Acta. affinity of one is to membrane and but the binding of modules to the membrane is to activate the kinase This is by the PKC which are activated by signals that diacylglycerol and Protein kinase C as a molecular for and diacylglycerol a for the cellular 2006; the affinity of membrane-targeting and is to membrane only one second messenger is has membrane binding on the of second messengers the kinase is recruited to membranes a membrane which the to of the kinase binding on the of Protein kinase and by and which the membrane of the tyrosine kinase is a of for this and of comprise the two membrane-targeting modules. with the domains of PKC membranes with affinity to membrane on the of but the of membrane binding on the of and of the of the This of two modules in control of membrane the of a in either diacylglycerol or the affinity of PKC for membranes to the in the of of the the to membrane from the membrane. the of two membrane-targeting modules is to signaling and to provide high in the membrane in response to appropriate membrane-targeting modules with the appropriate lipid allosterically the of PKC and but by mechanisms for the of the membrane-targeting modules on the membrane, with high a that from the binding and This acutely on lipid the of the on membranes the of of two Akt is in PKC is is of lipid is acutely controlled by the of lipid allosterically the of a lipid allosterically the of that Akt from lipid that control the of PKC and Akt are in the and activation of kinase is PKC is the activation the and the by mechanisms that on the kinases and a the kinase protein kinase and protein kinase of the kinases by protein kinase C as a a binding of a and that the function of in PKC and Akt and to the in in which the that of in and for PKC is the binding of to the of that the of the that the membrane is the membrane. and in its on the of the and domains to membranes the to the from the of the on the binding of PKC to the membrane, as which bind the with two of affinity are to recruit PKC to membranes with high affinity to the in the of binding to high of can recruit PKC to membranes and in the of PKC on and off membranes in response to second messenger the is to and the molecular which the to and the of for lipid binding allosterically the of the by the and Akt are by two mechanisms in lipid second messengers and of the of PKC with the membrane in in which the is from the of the kinase and the kinase, is on the the activation in PKC is to be first and to be followed by two the the in PKC and the in PKC of the on the this of the PKC is the in a in which the the the kinase of that of in of PKC to the membrane binding of to the PKC to the membrane by a where diacylglycerol via the the and domains on the membrane in a membrane that in of the signaling of Membrane is and by in second messenger is that membrane binding in of PKC by protein and and of to the on the C to and the of that the is and the and are PKC that is not by is by as the and of the of Akt is on the in by a that on that phosphatidylinositol-3,4,5-trisphosphate (PIP3) the and recruit Akt to the plasma membrane the activation in by in and on the in of Akt is in and throughout the to signaling is by of the lipid second messengers and of in by the protein which directly the and Akt are by two mechanisms in lipid second messengers and of the of PKC with the membrane in in which the is from the of the kinase and the kinase, is on the the activation in PKC is to be first and to be followed by two the the in PKC and the in PKC of the on the this of the PKC is the in a in which the the the kinase of that of in of PKC to the membrane binding of to the PKC to the membrane by a where diacylglycerol via the the and domains on the membrane in a membrane that in of the signaling of Membrane is and by in second messenger is that membrane binding in of PKC by protein and and of to the on the C to and the of that the is and the and are PKC that is not by is by as the and of the of Akt is on the in by a that on that phosphatidylinositol-3,4,5-trisphosphate (PIP3) the and recruit Akt to the plasma membrane the activation in by in and on the in of Akt is in and throughout the to signaling is by of the lipid second messengers and of in by the protein which directly the of in Akt activation is to Akt is only one the by a that that of on of and of Akt and protein kinase membrane binding the of Akt that the activation for by the same kinase that this is followed by of the Akt is in and throughout the in by the protein signaling by the for lipid binding the in Akt in a of the of the of PKC signaling Protein kinase C as a molecular for and diacylglycerol of the of the of protein kinase C in proteins with protein domains from protein kinase C as for diacylglycerol signaling in by protein kinase protein kinase C to PKC PKC and the second messengers diacylglycerol and has that PKC a of activation on the cellular location protein kinase C to in 2006; response to as that activate and and diacylglycerol to are recruited and activated the plasma membrane, with the of activation the in protein kinase C to in 2006; This in is followed by a in plasma membrane and is the diacylglycerol that the of in which in in PKC diacylglycerol PKC can membrane but the on are high and the is the is from the or that the is not the the by protein kinase the are with the plasma membrane in of this lipid second messenger are the with the plasma membrane. of diacylglycerol in a PKC to not only is there of which affinity for diacylglycerol of a for binding to diacylglycerol J.H. membrane affinity of the of protein kinase C for the of of its in membrane in the protein kinase C to cellular diacylglycerol but the is the plasma membrane protein kinase C to in 2006; activation of PKC and Akt is by second messenger but only PKC in second messenger for activity. the in diacylglycerol the plasma membrane and PKC the plasma membrane by for and PKC activity. activation is by which PKC to the plasma membrane, but on from protein kinase C to in 2006; in the plasma membrane Akt the plasma membrane in the and in the from of protein kinase signaling by a for Akt a of that from the plasma membrane to the of protein kinase signaling by a of Akt activation the plasma membrane with that of to the with a of is in the with a of the plasma membrane and is that in the is second messengers of signals that control growth and cellular binding of protein kinases to lipid second messengers as a first to transduce the of the cell. of kinases is and of this in most notably in on a Protein kinase C and diacylglycerol in This review has two of the major lipid-regulated PKC and membrane-targeting modules to directly bind lipid second that Cellular membranes form a platform of intense signaling activity. Serving as the site where extracellular signals are first received by the cell, they not only recruit and activate effector molecules, but they also provide a spring board to launch activated effector molecules throughout the cell. Protein kinases comprise one of the most common classes of effector molecules that transduce signals emanating from the plasma membrane. These kinases can be embedded in the plasma membrane, exemplified by the tyrosine kinase growth factor receptors, or can be either soluble or amphipathic membrane proteins that translocate on and off cellular membranes in response to appropriate signals. Soluble proteins are recruited to membranes by protein scaffolds, but there exists a class of amphipathic membrane kinases whose members directly bind lipid second messengers via specific membrane-targeting modules. It is this latter class of lipid-controlled kinases that forms the focus of this the enormity of the kinome, few kinases (approximately 10%) directly bind and transduce lipid second messenger signals. Yet they transduce signals in two of the most pivotal signaling pathways in cells, notably the diacylglycerol and phosphatidylinositol 3 kinase pathways. To this end, lipid second messenger-regulated protein kinases contain modules that bind with high specificity and affinity to the relevant lipid second messengers (1Hurley J.H. Membrane binding domains.Biochim. Biophys. Acta. 2006; 1761: 805-811Crossref Membrane by the is the diacylglycerol J.H. and function of protein kinase C and the or modules as the J.H. phosphatidylinositol domains as the can in membrane of the kinase by with specific in by a J.H. by membrane Protein kinase two lipid second messenger-regulated kinases contain one or membrane-targeting modules whose membrane in protein kinase by the of of the major lipid second protein kinases. the of protein kinase which to the kinase of the kinome, kinases are members of the (protein kinases and of the kinome, where they for of the members of this the protein kinase C (PKC) of which there are and Protein kinase C and lipid signaling for cellular and of protein kinase and PKC contain domains and transduce signals that diacylglycerol Protein kinase also a and in the of and PKC 2006; of this in PKC and in not bind diacylglycerol J.H. and function of protein kinase C they the affinity of domains for the and domains of protein kinase C are membrane with specificity for by the kinases in this contain domains that members of the Akt of kinases contain a that phosphatidylinositol-3,4,5-trisphosphate as one of the major mechanisms to transduce signals that activate phosphatidylinositol 3 kinase is also in one of the protein kinase of in and Biophys. Acta. the kinase for most of the kinases in also has a with high this kinase is in cells, with signaling kinase of in and Biophys. Acta. the of kinase domains bind a is in the kinase, as a and and of protein is the most to by protein but that kinases as a the affinity of the for to where this lipid and protein on a 2006; kinases a the Protein kinase two and the in and Protein the of PKC this in a the of PKC and protein kinase the not to function as a It is that for of the major modules the and there that not bind as exemplified by the in and protein kinase the domains in PKC and and the in common in the of amphipathic membrane kinases that translocate on and off membranes is the of two membrane-targeting domains Protein kinase a for of protein function by two membrane-targeting Biophys. Acta. affinity of one is to membrane and but the binding of modules to the membrane is to activate the kinase This is by the PKC which are activated by signals that diacylglycerol and Protein kinase C as a molecular for and diacylglycerol a for the cellular 2006; the affinity of membrane-targeting and is to membrane only one second messenger is has membrane binding on the of second messengers the kinase is recruited to membranes a membrane which the to of the kinase binding on the of Protein kinase and by and which the membrane of the tyrosine kinase is a of for this and of comprise the two membrane-targeting modules. with the domains of PKC membranes with affinity to membrane on the of but the of membrane binding on the of and of the of the This of two modules in control of membrane the of a in either diacylglycerol or the affinity of PKC for membranes to the in the of of the the to membrane from the membrane. the of two membrane-targeting modules is to signaling and to provide high in the membrane in response to appropriate signals. the of of the major lipid second protein kinases. the of protein kinase which to the kinase of the kinome, kinases are members of the (protein kinases and of the kinome, where they for of the members of this the protein kinase C (PKC) of which there are and Protein kinase C and lipid signaling for cellular and of protein kinase and PKC contain domains and transduce signals that diacylglycerol Protein kinase also a and in the of and PKC 2006; of this in PKC and in not bind diacylglycerol J.H. and function of protein kinase C they the affinity of domains for the and domains of protein kinase C are membrane with specificity for by the kinases in this contain domains that members of the Akt of kinases contain a that phosphatidylinositol-3,4,5-trisphosphate as one of the major mechanisms to transduce signals that activate phosphatidylinositol 3 kinase is also in one of the protein kinase of in and Biophys. Acta. the kinase for most of the kinases in also has a with high this kinase is in cells, with signaling kinase of in and Biophys. Acta. the of kinase domains bind a is in the kinase, as a and and of protein is the most to by protein but that kinases as a the affinity of the for to where this lipid and protein on a 2006; kinases a the Protein kinase two and the in and Protein the of PKC this in a the of PKC and protein kinase the not to function as a It is that for of the major modules the and there that not bind as exemplified by the in and protein kinase the domains in PKC and and the in common in the of amphipathic membrane kinases that translocate on and off membranes is the of two membrane-targeting domains Protein kinase a for of protein function by two membrane-targeting Biophys. Acta. affinity of one is to membrane and but the binding of modules to the membrane is to activate the kinase This is by the PKC which are activated by signals that diacylglycerol and Protein kinase C as a molecular for and diacylglycerol a for the cellular 2006; the affinity of membrane-targeting and is to membrane only one second messenger is has membrane binding on the of second messengers the kinase is recruited to membranes a membrane which the to of the kinase binding on the of Protein kinase and by and which the membrane of the tyrosine kinase is a of for this and of comprise the two membrane-targeting modules. with the domains of PKC membranes with affinity to membrane on the of but the of membrane binding on the of and of the of the This of two modules in control of membrane the of a in either diacylglycerol or the affinity of PKC for membranes to the in the of of the the to membrane from the membrane. the of two membrane-targeting modules is to signaling and to provide high in the membrane in response to appropriate signals. PKC membrane-targeting modules with the appropriate lipid allosterically the of PKC and but by mechanisms for the of the membrane-targeting modules on the membrane, with high a that from the binding and This acutely on lipid the of the on membranes the of of two Akt is in PKC is is of lipid is acutely controlled by the of lipid allosterically the of a lipid allosterically the of that Akt from lipid that control the of PKC and Akt are in the and activation of kinase is PKC is the activation the and the by mechanisms that on the kinases and a the kinase protein kinase and protein kinase of the kinases by protein kinase C as a a binding of a and that the function of in PKC and Akt and to the in in which the that of in and for PKC is the binding of to the of that the of the that the membrane is the membrane. and in its on the of the and domains to membranes the to the from the of the on the binding of PKC to the membrane, as which bind the with two of affinity are to recruit PKC to membranes with high affinity to the in the of binding to high of can recruit PKC to membranes and in the of PKC on and off membranes in response to second messenger the is to and the molecular which the to and the of for lipid binding allosterically the of the by the and Akt are by two mechanisms in lipid second messengers and of the of PKC with the membrane in in which the is from the of the kinase and the kinase, is on the the activation in PKC is to be first and to be followed by two the the in PKC and the in PKC of the on the this of the PKC is the in a in which the the the kinase of that of in of PKC to the membrane binding of to the PKC to the membrane by a where diacylglycerol via the the and domains on the membrane in a membrane that in of the signaling of Membrane is and by in second messenger is that membrane binding in of PKC by protein and and of to the on the C to and the of that the is and the and are PKC that is not by is by as the and of the of Akt is on the in by a that on that phosphatidylinositol-3,4,5-trisphosphate (PIP3) the and recruit Akt to the plasma membrane the activation in by in and on the in of Akt is in and throughout the to signaling is by of the lipid second messengers and of in by the protein which directly the of in Akt activation is to Akt is only one the by a that that of on of and of Akt and protein kinase membrane binding the of Akt that the activation for by the same kinase that this is followed by of the Akt is in and throughout the in by the protein signaling by the for lipid binding the in Akt in a of the of the of PKC signaling Protein kinase C as a molecular for and diacylglycerol of the of the of protein kinase C in proteins with protein domains from protein kinase C as for diacylglycerol signaling in by protein kinase protein kinase C to PKC PKC and the second messengers diacylglycerol and has that PKC a of activation on the cellular location protein kinase C to in 2006; response to as that activate and and diacylglycerol to are recruited and activated the plasma membrane, with the of activation the in protein kinase C to in 2006; This in is followed by a in plasma membrane and is the diacylglycerol that the of in which in in PKC diacylglycerol PKC can membrane but the on are high and the is the is from the or that the is not the the by protein kinase the are with the plasma membrane in of this lipid second messenger are the with the plasma membrane. of diacylglycerol in a PKC to not only is there of which affinity for diacylglycerol of a for binding to diacylglycerol J.H. membrane affinity of the of protein kinase C for the of of its in membrane in the protein kinase C to cellular diacylglycerol but the is the plasma membrane protein kinase C to in 2006; activation of PKC and Akt is by second messenger but only PKC in second messenger for activity. the in diacylglycerol the plasma membrane and PKC the plasma membrane by for and PKC activity. activation is by which PKC to the plasma membrane, but on from protein kinase C to in 2006; in the plasma membrane Akt the plasma membrane in the and in the from of protein kinase signaling by a for Akt a of that from the plasma membrane to the of protein kinase signaling by a of Akt activation the plasma membrane with that of to the with a of is in the with a of the plasma membrane and is that in the is membrane-targeting modules with the appropriate lipid allosterically the of PKC and but by mechanisms for the of the membrane-targeting modules on the membrane, with high a that from the binding and This acutely on lipid the of the on membranes the of of two Akt is in PKC is is of lipid is acutely controlled by the of lipid allosterically the of a lipid allosterically the of that Akt from lipid that control the of PKC and Akt are in the and activation of kinase is PKC is the activation the and the by mechanisms that on the kinases and a the kinase protein kinase and protein kinase of the kinases by protein kinase C as a a binding of a and that the function of in PKC and Akt and to the in in which the that of in and for PKC is the binding of to the of that the of the that the membrane is the membrane. and in its on the of the and domains to membranes the to the from the of the on the binding of PKC to the membrane, as which bind the with two of affinity are to recruit PKC to membranes with high affinity to the in the of binding to high of can recruit PKC to membranes and in the of PKC on and off membranes in response to second messenger the is to and the molecular which the to and the of for lipid binding allosterically the of the by the of in Akt activation is to Akt is only one the by a that that of on of and of Akt and protein kinase membrane binding the of Akt that the activation for by the same kinase that this is followed by of the Akt is in and throughout the in by the protein signaling by the for lipid binding the in Akt in a of the of the of PKC signaling Protein kinase C as a molecular for and diacylglycerol of the of the of protein kinase C in proteins with protein domains from protein kinase C as for diacylglycerol signaling in by protein kinase protein kinase C to PKC PKC and the second messengers diacylglycerol and has that PKC a of activation on the cellular location protein kinase C to in 2006; response to as that activate and and diacylglycerol to are recruited and activated the plasma membrane, with the of activation the in protein kinase C to in 2006; This in is followed by a in plasma membrane and is the diacylglycerol that the of in which in in PKC diacylglycerol PKC can membrane but the on are high and the is the is from the or that the is not the the by protein kinase the are with the plasma membrane in of this lipid second messenger are the with the plasma membrane. of diacylglycerol in a PKC to not only is there of which affinity for diacylglycerol of a for binding to diacylglycerol J.H. membrane affinity of the of protein kinase C for the of of its in membrane in the protein kinase C to cellular diacylglycerol but the is the plasma membrane protein kinase C to in 2006; for Akt a of that from the plasma membrane to the of protein kinase signaling by a of Akt activation the plasma membrane with that of to the with a of is in the with a of the plasma membrane and is that in the is second messengers of signals that control growth and cellular binding of protein kinases to lipid second messengers as a first to transduce the of the cell. of kinases is and of this in most notably in on a Protein kinase C and diacylglycerol in This review has two of the major lipid-regulated PKC and membrane-targeting modules to directly bind lipid second that second messengers of signals that control growth and cellular binding of protein kinases to lipid second messengers as a first to transduce the of the cell. of kinases is and of this in most notably in on a Protein kinase C and diacylglycerol in This review has two of the major lipid-regulated PKC and membrane-targeting modules to directly bind lipid second that