Design Logic of a Cannabinoid Receptor Signaling Network That Triggers Neurite Outgrowth

Cannabinoid receptor 1 (CB1R) regulates neuronal differentiation. To understand the logic underlying decision-making in the signaling network controlling CB1R-induced neurite outgrowth, we profiled the activation of several hundred transcription factors after cell stimulation. We assembled an in silico signaling network by connecting CB1R to 23 activated transcription factors. Statistical analyses of this network predicted a role for the breast cancer 1 protein BRCA1 in neuronal differentiation and a new pathway from CB1R through phosphoinositol 3-kinase to the transcription factor paired box 6 (PAX6). Both predictions were experimentally confirmed. Results of transcription factor activation experiments that used pharmacological inhibitors of kinases revealed a network organization of partial OR gates regulating kinases stacked above AND gates that control transcription factors, which together allow for distributed decision-making in CB1R-induced neurite outgrowth.

[1]  B. Koller,et al.  Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities , 1996, Nature Genetics.

[2]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[3]  Stephen J. Smith,et al.  Evidence for a Role of Dendritic Filopodia in Synaptogenesis and Spine Formation , 1996, Neuron.

[4]  Duncan J. Watts,et al.  Collective dynamics of ‘small-world’ networks , 1998, Nature.

[5]  S. Grant,et al.  Proteomic analysis of NMDA receptor–adhesion protein signaling complexes , 2000, Nature Neuroscience.

[6]  Y. Houvras,et al.  BRCA1 Physically and Functionally Interacts with ATF1* , 2000, The Journal of Biological Chemistry.

[7]  E. Rosen,et al.  Constitutive activation of JAK–STAT3 signaling by BRCA1 in human prostate cancer cells , 2001, FEBS letters.

[8]  Gary D Bader,et al.  BIND--The Biomolecular Interaction Network Database. , 2001, Nucleic acids research.

[9]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[10]  Prahlad T. Ram,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2002, Science.

[11]  Ashok R Venkitaraman,et al.  Cancer Susceptibility and the Functions of BRCA1 and BRCA2 , 2002, Cell.

[12]  H. Avraham,et al.  Extracellular Matrix Enhances Heregulin-Dependent BRCA1 Phosphorylation and Suppresses BRCA1 Expression through Its C Terminus , 2003, Molecular and Cellular Biology.

[13]  R. Segal,et al.  Selectivity in neurotrophin signaling: theme and variations. , 2003, Annual review of neuroscience.

[14]  D. Pilz,et al.  Neuronal migration defect in a BRCA1 gene carrier: possible focal nullisomy? , 2003, Journal of medical genetics.

[15]  Adam J. Smith,et al.  The Database of Interacting Proteins: 2004 update , 2004, Nucleic Acids Res..

[16]  E. Birney,et al.  Reactome: a knowledgebase of biological pathways , 2004, Nucleic Acids Research.

[17]  R. Iyengar,et al.  The Gαo/i-coupled Cannabinoid Receptor-mediated Neurite Outgrowth Involves Rap Regulation of Src and Stat3* , 2005, Journal of Biological Chemistry.

[18]  R. Iyengar,et al.  Cannabinoid Receptor-induced Neurite Outgrowth Is Mediated by Rap1 Activation through Gαo/i-triggered Proteasomal Degradation of Rap1GAPII* , 2005, Journal of Biological Chemistry.

[19]  Serhiy Souchelnytskyi,et al.  TGFβ1/Smad3 counteracts BRCA1-dependent repair of DNA damage , 2005, Oncogene.

[20]  L. Van Aelst,et al.  The role of the Rho GTPases in neuronal development. , 2005, Genes & development.

[21]  Prahlad T. Ram,et al.  Formation of Regulatory Patterns During Signal Propagation in a Mammalian Cellular Network , 2005, Science.

[22]  B. Castle,et al.  BRCA1 mutation and neuronal migration defect: implications for chemoprevention , 2005, Journal of Medical Genetics.

[23]  K. S. Deshpande,et al.  Human protein reference database—2006 update , 2005, Nucleic Acids Res..

[24]  Vivien Chevaleyre,et al.  Endocannabinoid-mediated synaptic plasticity in the CNS. , 2006, Annual review of neuroscience.

[25]  David M. Livingston,et al.  The BRCA1/BARD1 Heterodimer Modulates Ran-Dependent Mitotic Spindle Assembly , 2006, Cell.

[26]  M. Clagett-Dame,et al.  Role of all-trans retinoic acid in neurite outgrowth and axonal elongation. , 2006, Journal of neurobiology.

[27]  A. Ashworth,et al.  The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability , 2006, Oncogene.

[28]  Mike Tyers,et al.  BioGRID: a general repository for interaction datasets , 2005, Nucleic Acids Res..

[29]  E. Martí,et al.  The TGFβ intracellular effector Smad3 regulates neuronal differentiation and cell fate specification in the developing spinal cord , 2007, Development.

[30]  D. Centonze,et al.  The endocannabinoid system in targeting inflammatory neurodegenerative diseases. , 2007, Trends in pharmacological sciences.

[31]  B. Ruggeri,et al.  PAX genes: roles in development, pathophysiology, and cancer. , 2007, Biochemical pharmacology.

[32]  Yan Liu,et al.  Protein Phosphatase-1 Modulates the Function of Pax-6, a Transcription Factor Controlling Brain and Eye Development* , 2007, Journal of Biological Chemistry.

[33]  Avi Ma'ayan,et al.  Genes2Networks: connecting lists of gene symbols using mammalian protein interactions databases , 2007, BMC Bioinformatics.

[34]  Y. Zhang,et al.  IntAct—open source resource for molecular interaction data , 2006, Nucleic Acids Res..

[35]  K. Mackie,et al.  The emerging functions of endocannabinoid signaling during CNS development. , 2007, Trends in pharmacological sciences.

[36]  Maria Victoria Schneider,et al.  MINT: a Molecular INTeraction database. , 2002, FEBS letters.