title: Cellular phosphatases facilitate combinatorial processing of receptor-activated signals.
abstract: BACKGROUND
  Although reciprocal regulation of protein phosphorylation represents a key aspect of signal transduction, a larger perspective on how these various interactions integrate to contribute towards signal processing is presently unclear. For example, a key unanswered question is that of how phosphatase-mediated regulation of phosphorylation at the individual nodes of the signaling network translates into modulation of the net signal output and, thereby, the cellular phenotypic response.
  
  
  RESULTS
  To address the above question we, in the present study, examined the dynamics of signaling from the B cell antigen receptor (BCR) under conditions where individual cellular phosphatases were selectively depleted by siRNA. Results from such experiments revealed a highly enmeshed structure for the signaling network where each signaling node was linked to multiple phosphatases on the one hand, and each phosphatase to several nodes on the other. This resulted in a configuration where individual signaling intermediates could be influenced by a spectrum of regulatory phosphatases, but with the composition of the spectrum differing from one intermediate to another. Consequently, each node differentially experienced perturbations in phosphatase activity, yielding a unique fingerprint of nodal signals characteristic to that perturbation. This heterogeneity in nodal experiences, to a given perturbation, led to combinatorial manipulation of the corresponding signaling axes for the downstream transcription factors.
  
  
  CONCLUSIONS
  Our cumulative results reveal that it is the tight integration of phosphatases into the signaling network that provides the plasticity by which perturbation-specific information can be transmitted in the form of a multivariate output to the downstream transcription factor network. This output in turn specifies a context-defined response, when translated into the resulting gene expression profile.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, 110067, India. dhirajkrverma@gmail.com
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Kumar
authors.forename: Raina
authors.initials: R
authors.lastname: Dua
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Srikanth
authors.forename: Shilpi
authors.initials: S
authors.lastname: Jayaswal
authors.forename: Zaved
authors.initials: Z
authors.lastname: Siddiqui
authors.forename: Kanury V S
authors.initials: KV
authors.lastname: Rao
references.citation: Science. 2002 Aug 9;297(5583):1018-23
references.pmid: 12169734
references.citation: Mol Syst Biol. 2007;3:150
references.pmid: 18059445
references.citation: Cell Calcium. 2007 Aug;42(2):145-56
references.pmid: 17572487
references.citation: Physiol Rev. 2004 Jan;84(1):1-39
references.pmid: 14715909
references.citation: Science. 2005 Dec 9;310(5754):1646-53
references.pmid: 16339439
references.citation: J Immunol. 2003 Jun 1;170(11):5630-5
references.pmid: 12759443
references.citation: J Theor Biol. 2004 Sep 7;230(1):119-32
references.pmid: 15276005
references.citation: Nat Rev Mol Cell Biol. 2006 Nov;7(11):820-8
references.pmid: 17057752
references.citation: J Biol Chem. 1999 Oct 22;274(43):30353-6
references.pmid: 10521409
references.citation: FEBS J. 2005 Jan;272(1):244-58
references.pmid: 15634347
references.citation: Immunity. 2006 Nov;25(5):701-15
references.pmid: 17098202
references.citation: Nat Rev Mol Cell Biol. 2006 Nov;7(11):813-9
references.pmid: 17006434
references.citation: J Biol Chem. 1995 Jul 14;270(28):16483-6
references.pmid: 7622446
references.citation: J Cell Sci. 2006 Nov 15;119(Pt 22):4607-15
references.pmid: 17093265
references.citation: EMBO J. 2006 Feb 22;25(4):811-21
references.pmid: 16437157
references.citation: J Clin Invest. 2002 Jan;109(1):9-14
references.pmid: 11781344
references.citation: Curr Opin Cell Biol. 1997 Apr;9(2):240-6
references.pmid: 9069263
references.citation: Annu Rev Biophys Biomol Struct. 1998;27:133-64
references.pmid: 9646865
references.citation: Mol Cell. 2002 May;9(5):957-70
references.pmid: 12049733
references.citation: J Endocrinol. 2005 Apr;185(1):19-33
references.pmid: 15817824