Editors' ChoiceSignal Mediation

Cell Signals Show Their Where's

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Science's STKE  05 Mar 2002:
Vol. 2002, Issue 122, pp. tw97
DOI: 10.1126/stke.2002.122.tw97

Two studies have used fluorescence resonance energy transfer (FRET) to find out how and where the molecular partners of cell signaling get together in cells. Phosphotyrosine phosphatases like PTP1B (protein tyrosine phosphatase-1B) oppose the signaling of activated receptor tyrosine kinases by dephosphorylating tyrosine residues. Haj et al. (see the Perspective by Gill) imaged a fluorescently tagged mutant of PTP1B and found that it interacted with epidermal- and platelet-derived growth factor in living mouse fibroblasts at the cytoplasmic surface of the endoplasmic reticulum. This interaction was maximal about 30 min after the receptors were stimulated and required endocytosis of receptors from the cell surface. Thus, internalization of receptors, which is required for some forms of signaling, also seems to target the receptor to a dephosphorylation compartment. In cardiac myocytes, the second messenger adenosine 3′,5′-monophosphate (cAMP) somehow mediates distinct signals from different receptors, possibly through the spatial localization of these signals. Indeed, the primary target of cAMP, protein kinase A (PKA), and the enzyme that produces cAMP, adenylyl cyclase, are both localized to the T tubules of myocytes that store Ca2+, which is required to stimulate contraction. Zaccolo and Pozzan now report that PKA is activated in response to stimulation of β-adrenergic receptors in small microdomains around the T tubules. Diffusion of cAMP appears to be limited to a few micrometers by high activity of phosphodiesterases that degrade cAMP. Localization of PKA by A-kinase anchoring proteins (AKAPs) is required to allow activation.

F. G. Haj, P. J. Verveer, A. Squire, B. G. Neel, P. I. H. Bastiaens, Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295, 1708-1711 (2002). [Abstract] [Full Text]

G. N. Gill, A pit stop at the ER. Science 295, 1654-1655 (2002). [Full Text]

M. Zaccolo, T. Pozzan, Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295, 1711-1715 (2002). [Abstract] [Full Text]

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