A Computational Analysis of the Dynamic Roles of Talin, Dok1, and PIPKI for Integrin Activation

Integrin signaling regulates cell migration and plays a pivotal role in developmental processes and cancer metastasis. Integrin signaling has been studied extensively and much data is available on pathway components and interactions. Yet the data is fragmented and an integrated model is missing. We use a rule-based modeling approach to integrate available data and test biological hypotheses regarding the role of talin, Dok1 and PIPKI in integrin activation. The detailed biochemical characterization of integrin signaling provides us with measured values for most of the kinetics parameters. However, measurements are not fully accurate and the cellular concentrations of signaling proteins are largely unknown and expected to vary substantially across different cellular conditions. By sampling model behaviors over the physiologically realistic parameter range we find that the model exhibits only two different qualitative behaviors and these depend mainly on the relative protein concentrations, which offers a powerful point of control to the cell. Our study highlights the necessity to characterize model behavior not for a single parameter optimum, but to identify parameter sets that characterize different signaling modes.

[1]  G. I. Bell.  Models for the specific adhesion of cells to cells. , 1978, Science.

[2]  M. Ginsberg,et al.  Specific and saturable binding of plasma fibronectin to thrombin-stimulated human platelets. , 1981, The Journal of biological chemistry.

[3]  N. Neff,et al.  A Monoclonal Antibody Detaches Muscle from Extracellular Matrices Embryonic Skeletal , 2003 .

[4]  K. Yamada,et al.  The interaction of fibronectin fragments with fibroblastic cells. , 1985, The Journal of biological chemistry.

[5]  S. C. Kuo,et al.  Relationship between receptor/ligand binding affinity and adhesion strength. , 1993, Biophysical journal.

[6]  M. Ginsberg,et al.  Affinity modulation of integrin alpha 5 beta 1: regulation of the functional response by soluble fibronectin , 1993, The Journal of cell biology.

[7]  Charis Eng,et al.  Catalytic specificity of protein-tyrosine kinases is critical for selective signalling , 1995, Nature.

[8]  W. Goldmann,et al.  Determination of the affinity of talin and vinculin to charged lipid vesicles: a light scatter study , 1995, FEBS letters.

[9]  M. Ginsberg,et al.  Dynamic regulation of integrins , 1995, Stem cells.

[10]  J. Hurley,et al.  Structure of Type IIβ Phosphatidylinositol Phosphate Kinase A Protein Kinase Fold Flattened for Interfacial Phosphorylation , 1998, Cell.

[11]  Y. Jiao,et al.  Adhesion energy of receptor-mediated interaction measured by elastic deformation. , 1999, Biophysical journal.

[12]  G. Nemerow,et al.  Mechanisms and Consequences of Affinity Modulation of Integrin αVβ3 Detected with a Novel Patch-engineered Monovalent Ligand* , 1999, The Journal of Biological Chemistry.

[13]  G. Nemerow,et al.  Mechanisms and consequences of affinity modulation of integrin alpha(V)beta(3) detected with a novel patch-engineered monovalent ligand. , 1999, The Journal of biological chemistry.

[14]  J. Mizuguchi,et al.  Fibrinogen Binds to Integrin α5β1via the Carboxyl-Terminal RGD Site of the Aα-Chain , 2000 .

[15]  J. Mizuguchi,et al.  Fibrinogen binds to integrin alpha(5)beta(1) via the carboxyl-terminal RGD site of the Aalpha-chain. , 2000, Journal of biochemistry.

[16]  A. Galmiche,et al.  Conformation, Localization, and Integrin Binding of Talin Depend on Its Interaction with Phosphoinositides* , 2001, The Journal of Biological Chemistry.

[17]  A. Huttenlocher,et al.  Integrin-mediated adhesion regulates cell polarity and membrane protrusion through the Rho family of GTPases. , 2001, Molecular biology of the cell.

[18]  B. Yaspan,et al.  Calpain cleavage promotes talin binding to the beta 3 integrin cytoplasmic domain. , 2001, The Journal of biological chemistry.

[19]  David A. Calderwood,et al.  The Phosphotyrosine Binding-like Domain of Talin Activates Integrins* , 2002, The Journal of Biological Chemistry.

[20]  Pietro De Camilli,et al.  Recruitment and regulation of phosphatidylinositol phosphate kinase type 1γ by the FERM domain of talin , 2002, Nature.

[21]  K. Ling,et al.  Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions. , 2002, Nature.

[22]  K. Ling,et al.  Type Iγ phosphatidylinositol phosphate kinase targets and regulates focal adhesions , 2002, Nature.

[23]  D. Taverna,et al.  The diverse roles of integrins and their ligands in angiogenesis. , 2002, Cold Spring Harbor symposia on quantitative biology.

[24]  Clive R. Bagshaw,et al.  Phosphatidylinositol phosphate kinase type 1gamma and beta1-integrin cytoplasmic domain bind to the same region in the talin FERM domain. , 2003, The Journal of biological chemistry.

[25]  Clive R. Bagshaw,et al.  Phosphatidylinositol Phosphate Kinase Type 1γ and β1-Integrin Cytoplasmic Domain Bind to the Same Region in the Talin FERM Domain* , 2003, Journal of Biological Chemistry.

[26]  S. Harrison,et al.  Variation on an Src-like Theme , 2003, Cell.

[27]  D. Mosher,et al.  Tyrosine phosphorylation of type Iγ phosphatidylinositol phosphate kinase by Src regulates an integrin–talin switch , 2003, The Journal of cell biology.

[28]  R. Liddington,et al.  Talin Binding to Integrin ß Tails: A Final Common Step in Integrin Activation , 2003, Science.

[29]  J. Brugge,et al.  Src kinase activation by direct interaction with the integrin β cytoplasmic domain , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Hiroaki Kitano,et al.  The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models , 2003, Bioinform..

[31]  Pierre Bongrand,et al.  Beta-1 integrin-mediated adhesion may be initiated by multiple incomplete bonds, thus accounting for the functional importance of receptor clustering. , 2004, Biophysical journal.

[32]  Integrin activation , 2004, Journal of Cell Science.

[33]  Mark Ellisman,et al.  Spatial mapping of integrin interactions and dynamics during cell migration by Image Correlation Microscopy , 2004, Journal of Cell Science.

[34]  R. Roskoski,et al.  Src protein-tyrosine kinase structure and regulation. , 2004, Biochemical and biophysical research communications.

[35]  L. Maile,et al.  DOK1 Mediates SHP-2 Binding to the αVβ3 Integrin and Thereby Regulates Insulin-like Growth Factor I Signaling in Cultured Vascular Smooth Muscle Cells* , 2005, Journal of Biological Chemistry.

[36]  M. Arnaout,et al.  Integrin structure, allostery, and bidirectional signaling. , 2005, Annual review of cell and developmental biology.

[37]  R. Liddington,et al.  Structural Basis for Phosphatidylinositol Phosphate Kinase Type Iγ Binding to Talin at Focal Adhesions*[boxs] , 2005, Journal of Biological Chemistry.

[38]  M. Ginsberg,et al.  Specification of the Direction of Adhesive Signaling by the Integrin β Cytoplasmic Domain* , 2005, Journal of Biological Chemistry.

[39]  John M. Walker,et al.  Cell Migration , 2005, Methods in Molecular Biology™.

[40]  R. Irvine,et al.  The intracellular localisation and mobility of Type Iγ phosphatidylinositol 4P 5-kinase splice variants , 2006, FEBS letters.

[41]  Dagmar Iber,et al.  Integrin activation—the importance of a positive feedback , 2005, Bulletin of mathematical biology.

[42]  Carsten Peterson,et al.  A rate equation approach to elucidate the kinetics and robustness of the TGF-beta pathway. , 2006, Biophysical journal.

[43]  J. Stelling,et al.  Ensemble modeling for analysis of cell signaling dynamics , 2007, Nature Biotechnology.

[44]  D. Hilgemann.  Local PIP(2) signals: when, where, and how? , 2007, Pflugers Archiv : European journal of physiology.

[45]  Christopher R. Myers,et al.  Universally Sloppy Parameter Sensitivities in Systems Biology Models , 2007, PLoS Comput. Biol..

[46]  R. Liddington,et al.  Structural Basis of Integrin Activation by Talin , 2007, Cell.

[47]  Jun Qin,et al.  Structural basis for the autoinhibition of talin in regulating integrin activation. , 2008, Molecular cell.

[48]  I. Campbell,et al.  An Integrin Phosphorylation Switch , 2008, Journal of Biological Chemistry.

[49]  I. Campbell.  Studies of focal adhesion assembly. , 2008, Biochemical Society transactions.

[50]  M. Sheetz,et al.  Talin depletion reveals independence of initial cell spreading from integrin activation and traction , 2008, Nature Cell Biology.

[51]  Wei Liu,et al.  New PI(4,5)P2- and membrane proximal integrin–binding motifs in the talin head control β3-integrin clustering , 2009, The Journal of cell biology.

[52]  R. Fässler,et al.  The Tail of Integrins, Talin, and Kindlins , 2009, Science.

[53]  David S. Harburger,et al.  Kindlin-1 and -2 Directly Bind the C-terminal Region of β Integrin Cytoplasmic Tails and Exert Integrin-specific Activation Effects* , 2009, Journal of Biological Chemistry.

[54]  James R Faeder,et al.  Rule-based modeling of biochemical systems with BioNetGen. , 2009, Methods in molecular biology.

[55]  I. Campbell,et al.  β Integrin Tyrosine Phosphorylation Is a Conserved Mechanism for Regulating Talin-induced Integrin Activation* , 2009, The Journal of Biological Chemistry.

[56]  P. Sorger,et al.  Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis , 2009, Nature.

[57]  Michael L. Blinov,et al.  A Detailed Mathematical Model Predicts That Serial Engagement of IgE–FcεRI Complexes Can Enhance Syk Activation in Mast Cells , 2010, The Journal of Immunology.

[58]  F.,et al.  Specific and Saturable Binding of Plasma Fibronectin to Thrombin-stimulated Human Platelets ” , 2022 .