undergraduate research in computer science program director: dr. fatma mili ph.d
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Undergraduate Research in Undergraduate Research in Computer ScienceComputer Science
Program Director:Program Director:
Dr. Fatma Mili Ph.D.Dr. Fatma Mili Ph.D.
Application of a Coherence Application of a Coherence Network to Retinal Ganglion Network to Retinal Ganglion
Cell RegenerationCell RegenerationInvestigators:Investigators: Marianne Mara (MMarianne Mara (M22)) University of Michigan-DearbornUniversity of Michigan-Dearborn Noelle Nelson (NNoelle Nelson (N22) ) Oakland UniversityOakland University Advisors:Advisors: Dr. M. Zohdy PhD Dr. M. Zohdy PhD
Electrical and Computer Engineering Department Oakland UniversityElectrical and Computer Engineering Department Oakland University Dr. S. Chintala PhDDr. S. Chintala PhD Eye Research Institute Oakland UniversityEye Research Institute Oakland University
Research ObjectivesResearch Objectives
• Understand the basic mechanisms of retinal Understand the basic mechanisms of retinal ganglion cell regenerationganglion cell regeneration
• Apply a new extended coherence network Apply a new extended coherence network simulation to retinal ganglion cell interactions simulation to retinal ganglion cell interactions
• Study the important protein kinases involved in Study the important protein kinases involved in regeneration of retinal ganglion cellsregeneration of retinal ganglion cells
• Compare computer simulation (in silico) results Compare computer simulation (in silico) results to actual laboratory experiments performed at to actual laboratory experiments performed at the Eye Research Institutethe Eye Research Institute
Coherence NetworkCoherence Network
• A coherence network is made up of nodes A coherence network is made up of nodes (concepts) connected by arcs, that possibly (concepts) connected by arcs, that possibly carry real or complex weights (relationships), to carry real or complex weights (relationships), to arrive at coherent (consistent) solutions.arrive at coherent (consistent) solutions.
• We extended the basic coherence network to We extended the basic coherence network to include hierarchical classes of nodes and arcs in include hierarchical classes of nodes and arcs in order to better suit retinal ganglion cell protein order to better suit retinal ganglion cell protein interaction.interaction.
• Our additional contribution is to consider the Our additional contribution is to consider the Sigmoidal function for input/output relationships Sigmoidal function for input/output relationships again to suit retinal ganglion cell neuro-biologyagain to suit retinal ganglion cell neuro-biology
Applying the Extended Coherence Applying the Extended Coherence Network to Protein Kinase Network to Protein Kinase
InteractionInteraction• Network: Nodes represent the proteins and Network: Nodes represent the proteins and
associated kinases involved in retinal ganglion associated kinases involved in retinal ganglion cell regenerationcell regeneration
• Coherence represents consistent relationships Coherence represents consistent relationships that will show the qualitative and quantitative that will show the qualitative and quantitative effects of protein interactionseffects of protein interactions
• The extended coherence network model that we The extended coherence network model that we are developing describes the significance of are developing describes the significance of protein kinase pathways that may promote protein kinase pathways that may promote retinal ganglion cell regenerationretinal ganglion cell regeneration
Extended Coherent NetworkExtended Coherent Network
Class 3
Class 2
Class 1
Class 3
Class 1
Class 1
Class 2
Class 5
Class 4
Class 5
Class 5 Class 5
Class 4
Class 4
Legend
Class 1(Protein Kinase)
Class 2(Inhibitor)
Class 3(Protease)
Class 4Up Regulates
Class 5Down
Regulates
Active Node
A Protein Kinase and Inhibitor Interaction in A Protein Kinase and Inhibitor Interaction in a Retinal Ganglion Cell Linea Retinal Ganglion Cell Line
Staurosporine
PKC PKA
Down Regulates
tPAUp
RegulatesIn the presence
Of cAMP
PlaminogenActivatorInhibitor
Up Regulates
UpRegulates
Forms ComplexesTo Inactivate
DownRegulates
NeuriteOutgrowth
Protease Inhibitors
Protein Kinase
Biochemical Path Functional Outcome
Protease
Legend
Extended Coherent Network of the Extended Coherent Network of the Protein Kinase InteractionProtein Kinase Interaction
Legend
Class 1(Protein Kinase)
Class 2(Inhibitor)
Class 3(Protease)
Class 4Up Regulates
Class 5Down
Regulates
Active Node Staurosporine
PKC PKA
Down Regulates
tPA
UpRegulates
In the presenceOf cAMP
PlaminogenActivatorInhibitor
Up Regulates
UpRegulates
Forms ComplexesTo Inactivate
DownRegulates
Protease Inhibitors
Protein Kinase
Biochemical Path Functional Outcome
Protease
LegendProtein Kinase
CClass 1
PKAClass 1
Class 5(-1)
Class 4(1)
Class 5(-1)
StaurosporinClass 2
PlasminogenActivatorInhibitorClass 2
Class 4(1)
Class 4(1) tPA
Class 3
Class 5(-1)
Sigmoidal Functions Sigmoidal Functions
Anatomy of the Human EyeAnatomy of the Human Eye
Retinal Ganglion Cells
Bipolar Cells
Rod and Cone Cells
Horizontal CellsAmacrine Cells
Importance of Retinal Ganglion CellsImportance of Retinal Ganglion Cells• Major eye diseases like glaucoma are prevalent in the US and the world
population.
• Irreversible loss of retinal ganglion cells occurs in glaucoma
Nor
mal
Gla
ucom
a
Vision
Cross section of retinas
Laboratory Analysis Model for Retinal Laboratory Analysis Model for Retinal Ganglion CellsGanglion Cells
• Retinal ganglion cells in adult retina are terminally differentiated, do Retinal ganglion cells in adult retina are terminally differentiated, do not divide, survive for 1-3 generations in laboratory conditions, and not divide, survive for 1-3 generations in laboratory conditions, and cannot be used for long-term experiments. cannot be used for long-term experiments.
• RGC-5 cells are transformed cells, they take on many of the RGC-5 cells are transformed cells, they take on many of the characteristics of adult retinal ganglion cells, divide indefinitely characteristics of adult retinal ganglion cells, divide indefinitely under laboratory conditions, and therefore can be used to study the under laboratory conditions, and therefore can be used to study the mechanisms involved in regeneration of retinal ganglion cells. mechanisms involved in regeneration of retinal ganglion cells.
• Unlike adult retinal ganglion cells, RGC-5 cells divide in culture and Unlike adult retinal ganglion cells, RGC-5 cells divide in culture and appear as fibroblasts, and not like ganglion cells. appear as fibroblasts, and not like ganglion cells.
• However, RGC-5 cells can be programmed to behave like adult and However, RGC-5 cells can be programmed to behave like adult and differentiated ganglion cells after treatment with staurosporin (a differentiated ganglion cells after treatment with staurosporin (a chemical agent) that inhibits a number of intracellular protein chemical agent) that inhibits a number of intracellular protein kinases. kinases.
Undifferentiated Differentiated
RGC-5 cells treated with staurosporine to induce differentiation
As staurosporine inhibits a number of protein kinases, it is important to know which protein kinase (s) staurosporine inhibits, and which kinases
are responsible for inducing RGC-5 cells to differentiate.
CDK1/Cyclin B
AKT
cAMPPDE
Rho-Kinase
PKC
CAM
MLCK
PKA
PDGFR
EGFR
JAK-5
CDK5
CDK2/Cyclin A
MEK
cGMPPDE
Stauro-sporine
Protein Kinases
Protein Kinase Inhibitor
Known Protein Kinases Staurosporine Inhibits
Research ToolsResearch Tools
1.1. Matlab, and Matlab Toolboxes for developing an Matlab, and Matlab Toolboxes for developing an extended coherence networkextended coherence network
2.2. Microsoft Office Visio Microsoft Office Visio 3.3. Pathway Studio software Pathway Studio software 4.4. Designed experiments from Dr. Chintala’s Eye Designed experiments from Dr. Chintala’s Eye
Research Institute laboratoryResearch Institute laboratory5.5. NCBI Protein databanks with gene sequences, NCBI Protein databanks with gene sequences,
and related scientific journal articles and related scientific journal articles
Biochemical Biochemical PathsPaths
Staurosporine
PKC PKA
Down Regulates
tPA
UpRegulates
In the presenceOf cAMP
PlaminogenActivatorInhibitor
Up Regulates
UpRegulates
Forms ComplexesTo Inactivate
DownRegulates
Protease Inhibitors
Protein Kinase
Biochemical Path Functional Outcome
Protease
Legend
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
Staurosporine
CDK1CDK2
CDK5
JAK-5
EGFR
PDGFR
MLCK
CAM
RhoKinase
PKCcAMPPDE
cGMPPDE
MEK
AKT
DownRegulates
DownRegulates
PKA
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
DownRegulates
Stauro-sporine
CDK1CDK2
CDK5
JAK-5
EGFR
PDGFR
MLCK
CAM
RhoKinase
PKCcAMPPDE
cGMPPDE
MEK
AKT
DownRegulates
DownRegulates
PKA
DownRegulates Up
Regulates
PlasminogenActivatorInhibitor
tPA
Up Regulates
Inactivates
Up Regulates
Qualitative Analysis of a Coherent Qualitative Analysis of a Coherent NetworkNetwork
Legend
Class 1(Protein Kinase)
Class 2(Inhibitor)
Class 3(Protease)
Class 4Up Regulates
Class 5Down
Regulates
Active Node
Inactive Node
Protein Kinase
CClass 1
PKAClass 1
Class 5(-1)
Class 4(1)
Class 5(-1)
StaurosporinClass 2
PlasminogenActivatorInhibitorClass 2
Class 4(1)
Class 4(1) tPA
Class 3
Class 5(-1)
Qualitative Evaluation with an Qualitative Evaluation with an Extended Coherent NetworkExtended Coherent Network
Class 5(-1)
Class 4(1)
Class 4(1)
Class 4(1)
Class 5(-1)
Class 4(1)
Class 5(-1)
Class 4(1)
Class 5(-1)
PlasminogenActivatorInhibitorClass 2
Alpha-2Anti-plasmin
Class 2
MatrixMetallorotein
InhibitorClass2
UrokinasePlasminogen
ActivatorClass 3
PlasminogenClass 3
PlasminClass 3
Active MatrixMetalloProtein
Class 3
Active MatrixMetalloProtein
Class 3
Tissue Plasminogen
ActivatorClass 3
Legend
Class 1(Protein Kinase)
Class 2(Inhibitor)
Class 3(Protease)
Class 4Up Regulates
Class 5Down
Regulates
Active Node
Inactive Node
Qualitative Analysis of Staurosporine Qualitative Analysis of Staurosporine and the Protein Kinases it Inhibitsand the Protein Kinases it Inhibits
StaurosporineClass 2
MEKClass 1
MLCKClass 1
PDGFClass 1
EGFRClass 1
JAK-5Class 1
CDK2Class 1
AKTClass 1
CDK5Class 1
PKAClass 1
PKCClass 1
CAMClass 1
RhoKinase Class 1
cAMPPDE
Class 1
cGMPPDE
Class 1Cla
ss 5
(-1)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)Class
5(-1
)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)Cla
ss 5
(-1)
CDK1Class1
Class
5(-1
)
Legend
Class 1(Protei
n Kinase)
Class 2(Inhibit
or)
Class 3(Proteas
e)
Class 4Up
Regulate
Class 5Down
Regulate
Active Node
Inactive Node
Class
5(-1
)Cla
ss 5
(-1)
Class
5(-1
)
Class
5(-1
)
Qualitative Analysis of RGC-5 Cell Line Qualitative Analysis of RGC-5 Cell Line
Exposed to StaurosporineExposed to Staurosporine
StaurosporineClass 2
MEKClass 1
MLCKClass 1
PDGFClass 1
EGFRClass 1
JAK-5Class 1
CDK2Class 1
AKTClass 1
CDK5Class 1
PKAClass 1
PKCClass 1
CAMClass 1
RhoKinase Class 1
cAMPPDE
Class 1
cGMPPDE
Class 1
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)Class
5(-1
)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)
Class
5(-1
)Cla
ss 5
(-1)
CDK1Class1
Class
5(-1
)
Legend
Class 1(Protei
n Kinase)
Class 2(Inhibit
or)
Class 3(Proteas
e)
Class 4Up
Regulate
Class 5Down
Regulate
Active Node
Inactive Node
Class
5(-1
)Cla
ss 5
(-1)
Class
5(-1
)
Class
5(-1
)
tPAClass 3
PlasminogenActivatorInhibitorClass 3
Class
4(1)
Class
5(-1
)
Class
4(1)
Class
4(1)
Results from a Quantitative Results from a Quantitative Extended Coherence Network Extended Coherence Network
Simulation ISimulation I
Results from a Quantitative Results from a Quantitative Extended Coherence Network Extended Coherence Network
Simulation IISimulation II
ConclusionConclusion
We have gained a much better We have gained a much better understanding of RGC differentiation, understanding of RGC differentiation, regeneration, and neurite formation.regeneration, and neurite formation.Although it needs more work, our Although it needs more work, our coherence network was able to achieve coherence network was able to achieve some similarity to the laboratory generated some similarity to the laboratory generated data.data.At this point the At this point the in silicoin silico results seem to results seem to agree with cell line laboratory researchagree with cell line laboratory research
Further Research Further Research
As new data is discovered in relation to As new data is discovered in relation to the interaction of staurosporine and the interaction of staurosporine and protein kinases, the extended coherent protein kinases, the extended coherent network can be further explored.network can be further explored.
The extended coherent network may be The extended coherent network may be tested with well researched biochemical tested with well researched biochemical paths such as glycolysis and the Kreb’s paths such as glycolysis and the Kreb’s cycle.cycle.
Conference OpportunitiesConference Opportunities
American Chemical Society – Division of Biological American Chemical Society – Division of Biological Chemistry, XXVI Midwest Enzyme Chemistry Chemistry, XXVI Midwest Enzyme Chemistry Conference, September 30, 2006 Northwestern Conference, September 30, 2006 Northwestern University, Evanston, IL. University, Evanston, IL. www.midwestenzyme.orgwww.midwestenzyme.org
2006 Huntsville Simulation Conference, October 18 - 2006 Huntsville Simulation Conference, October 18 - 19, 2006 Huntsville, Alabama. www.scs.org.hsc19, 2006 Huntsville, Alabama. www.scs.org.hsc
ReferencesReferences20062006S. Chintala. Data from axon lengthening experiments with staurosporine, tissue plasminogen activator,and urokinase S. Chintala. Data from axon lengthening experiments with staurosporine, tissue plasminogen activator,and urokinase
plasminogen activator. Received June 29, 2006.plasminogen activator. Received June 29, 2006. The advisor provided data related to varying concentrations of staurosporine and the generationThe advisor provided data related to varying concentrations of staurosporine and the generation of tissue plasminogen activator and urokinase plasminogen activator.of tissue plasminogen activator and urokinase plasminogen activator.
S. Chintala. The emerging role of proteases in retinal ganglion cell death. Experimental Eye Research. Vol. 82, No.1, S. Chintala. The emerging role of proteases in retinal ganglion cell death. Experimental Eye Research. Vol. 82, No.1, pp. 5-12. , 2006.pp. 5-12. , 2006.
The article is a review of the known and proposed interplay of protein kinases, proteases, and inhibitors which The article is a review of the known and proposed interplay of protein kinases, proteases, and inhibitors which results in the destruction of retinal ganglion cells.results in the destruction of retinal ganglion cells.
L. Frassetto, C. Schlieve, C. Lievenen, A. Utter, M. Jones, N. Agarwal, & L. Levin. Kinase-dependent differentiation of L. Frassetto, C. Schlieve, C. Lievenen, A. Utter, M. Jones, N. Agarwal, & L. Levin. Kinase-dependent differentiation of
a retinal ganglion cell precursor. Inv. Ophth. & Vis. Sci. Vol. 47, No. 1, pp. 427-438, Jan. 2006.a retinal ganglion cell precursor. Inv. Ophth. & Vis. Sci. Vol. 47, No. 1, pp. 427-438, Jan. 2006. The authors report the effects of staurosporine induced differentiation in the RGC-5 cell line.The authors report the effects of staurosporine induced differentiation in the RGC-5 cell line.
K. Hu, J. Yang, S. Tanaka, S. Gonias, W. Mars, & Y. Liu. Tissue-type plasminogen activator acts as a cytokine that K. Hu, J. Yang, S. Tanaka, S. Gonias, W. Mars, & Y. Liu. Tissue-type plasminogen activator acts as a cytokine that triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. Jour. Of Bio. triggers intracellular signal transduction and induces matrix metalloproteinase-9 gene expression. Jour. Of Bio. Chem. Vol. 281, No. 4, pp. 2120-2127, Jan. 27, 2006.Chem. Vol. 281, No. 4, pp. 2120-2127, Jan. 27, 2006.
The articale describes the activation of matrix metalloproteins in light of the protein kinases inhibited.The articale describes the activation of matrix metalloproteins in light of the protein kinases inhibited.
Y. Yin, M. Henzl, B. Lorber, T. Nakazawa, T. Thomas, F. Jiang, R. Langer, & L. Benowitz. Oncomodulin is a Y. Yin, M. Henzl, B. Lorber, T. Nakazawa, T. Thomas, F. Jiang, R. Langer, & L. Benowitz. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nature Neuroscience. Vol. 9, No. 6, pp. macrophage-derived signal for axon regeneration in retinal ganglion cells. Nature Neuroscience. Vol. 9, No. 6, pp. June 2006.June 2006.
Tissue macrophages release oncomodulin which induces axon lengthening.Tissue macrophages release oncomodulin which induces axon lengthening.
References ContinuedReferences Continued20052005A. Davy, & P. Soriano. Ephrin signaling in vivo: Look both ways. Dev. Dynamics. Vol. 232, pp. 1-10, 2005.A. Davy, & P. Soriano. Ephrin signaling in vivo: Look both ways. Dev. Dynamics. Vol. 232, pp. 1-10, 2005. The authors describe embronic extension of the gangalion into the developing brain.The authors describe embronic extension of the gangalion into the developing brain. F. Mann, W. Harris, & C. Holt. New views on retinal axon development: a navigation guide. Int. Jour. Dev. Bio. Vol. 48, pp. F. Mann, W. Harris, & C. Holt. New views on retinal axon development: a navigation guide. Int. Jour. Dev. Bio. Vol. 48, pp.
957-964, 2004. 957-964, 2004. The authors describe the cell marker which assist in the “direction” of axon lengthening into the central nervous system.The authors describe the cell marker which assist in the “direction” of axon lengthening into the central nervous system.
X. Wang, S. Lee, K. Arai, S. Lee, K. Tsuji, G. Rebeck, & E. Lo. Lipoprotein receptor-mediated induction of matrix X. Wang, S. Lee, K. Arai, S. Lee, K. Tsuji, G. Rebeck, & E. Lo. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat. Med. Vol. 9, No. 10, pp. 1313-1317, Oct. 2003.metalloproteinase by tissue plasminogen activator. Nat. Med. Vol. 9, No. 10, pp. 1313-1317, Oct. 2003.
The article describes tPA as a signaling agent in combination with a lipoprotein receptor in retinal ganglion cell The article describes tPA as a signaling agent in combination with a lipoprotein receptor in retinal ganglion cell degradation by matrix metalloproteins. degradation by matrix metalloproteins.
20022002M. Aon, & S. Cortassa. Coherent and robust modulation of a metabolic network by cytosketal organization and dynamics. M. Aon, & S. Cortassa. Coherent and robust modulation of a metabolic network by cytosketal organization and dynamics.
Biophysical Chem. Vol. 97, Issue 2-3, pp. 213-231, June 2002.Biophysical Chem. Vol. 97, Issue 2-3, pp. 213-231, June 2002.
B. Patel & D. Vactor. Axon guidance: the cytoplasmic tail. Current Opinion in Cell Biology. Vol. 14, pp. 221-229, Jan. 30, B. Patel & D. Vactor. Axon guidance: the cytoplasmic tail. Current Opinion in Cell Biology. Vol. 14, pp. 221-229, Jan. 30, 2002.2002.
The Rho-kinase is investigated in light of the signaling necessary for axon lengthening .The Rho-kinase is investigated in light of the signaling necessary for axon lengthening .
References ContinuedReferences ContinuedR. Krishnamoorthy, P. Agarwal, G. Prasanna, K. Vopat, W. Lambert, H. Sheedlo, I. Pang, D. Shade, R. Wordinger, T. R. Krishnamoorthy, P. Agarwal, G. Prasanna, K. Vopat, W. Lambert, H. Sheedlo, I. Pang, D. Shade, R. Wordinger, T.
Yorio, A. Clark & N. Agarwal. Characterization of a transformed rat ganglion cell line. Mol. Brain Res. Vol. 86, Yorio, A. Clark & N. Agarwal. Characterization of a transformed rat ganglion cell line. Mol. Brain Res. Vol. 86, pp. 1-12, 2001.pp. 1-12, 2001.
The authors describe a cell line, RGC-5, which can be transformed for use in place of harvesting rat retinal The authors describe a cell line, RGC-5, which can be transformed for use in place of harvesting rat retinal ganglion cells.ganglion cells.
P. Thagard. Coherent and creative conceptual combinations. P. Thagard. Coherent and creative conceptual combinations. Creative Creative thought: An investigation of conceptual thought and structures.thought: An investigation of conceptual thought and structures. Washington, DC. American Psychological Association. pp. 29-141, 1997.Washington, DC. American Psychological Association. pp. 29-141, 1997.
F. Meggio, A. Donella Deana, M. Ruzzene, A. Brunati, L. Cesaro, B. Guerra, T. Meyer, H. Mett, D. Fabbro, P. Furet, G. F. Meggio, A. Donella Deana, M. Ruzzene, A. Brunati, L. Cesaro, B. Guerra, T. Meyer, H. Mett, D. Fabbro, P. Furet, G. Dobrowolska, & L. Pinna. Different susceptibility of protein kinases to staurosporine inhibition kinetic studies Dobrowolska, & L. Pinna. Different susceptibility of protein kinases to staurosporine inhibition kinetic studies and molecular bases for the resistance of protein kinase CK2. Eur. Jour. Biochem. Vol. 234, pp. 3317-322, and molecular bases for the resistance of protein kinase CK2. Eur. Jour. Biochem. Vol. 234, pp. 3317-322, 1995.1995.
The author describe the relative sensitivities of protein kinases to the inhibitory effects of staurosporine.The author describe the relative sensitivities of protein kinases to the inhibitory effects of staurosporine.
P. Leprince, C. Bonvoisin, B. Rogister, C. Mazy-Servais, & . Moonen. Protein kinase- and staurosporine-dependent P. Leprince, C. Bonvoisin, B. Rogister, C. Mazy-Servais, & . Moonen. Protein kinase- and staurosporine-dependent induction of neurite outgrowth and plasminogen activator activity in PC12 cells. Vol. 52, pp. 1399-1405, 1996.induction of neurite outgrowth and plasminogen activator activity in PC12 cells. Vol. 52, pp. 1399-1405, 1996.Protein kinase A and Protein kinase C interactions are studied to understand the effect of staurosporine on Protein kinase A and Protein kinase C interactions are studied to understand the effect of staurosporine on neurite lengthening in PC12 cell line.neurite lengthening in PC12 cell line.
N. Yanagihara, E. Tachikawa, F. Izumi, S. Yasugawa, H. Yammamoto, & E. Miyamoto. Staurosporine: An effictive N. Yanagihara, E. Tachikawa, F. Izumi, S. Yasugawa, H. Yammamoto, & E. Miyamoto. Staurosporine: An effictive Inhibitor for Ca+2/calmodulin-dependent protein kinase 2. Jour. Of Neurochem. Vol. 56, No. 1, pp. 294-298, Inhibitor for Ca+2/calmodulin-dependent protein kinase 2. Jour. Of Neurochem. Vol. 56, No. 1, pp. 294-298, 1991.1991.
The authors investigated the inhibitory role of staurosporine on the protein kinase CaThe authors investigated the inhibitory role of staurosporine on the protein kinase Ca +2+2/calmodulin-dependent /calmodulin-dependent protein kinase II.protein kinase II.
