|
Four different members of the Sprouty protein family block the cellular proliferation and differentiation induced by several different growth factors, including EGF and FGF. One mechanism by which Sprouty proteins inhibit signaling is through binding to Grb-2, a signaling intermediary between the tyrosine kinase growth factors and the Ras/map kinase pathway. Binding of Sprouty to Grb-2 prevents Grb-2 and Sos-1 from interacting with downstream signaling factors that activate Ras and map kinases, including Ras, Raf-1, Mek1, Erk1/2 and downstream transcription factors. The action of Sprouty as an inhibitor of this pathway requires Sprouty phosphorylation and membrane localization, at the site of the factors it interacts with. The inhibition of growth factor signaling by Sprouty is specific to the Ras pathway since the PI3 Kinase pathway responsible for cell survival signals from growth factor receptors is not inhibited by Sprouty. Tyrosine kinase activity of growth factor receptors is also not affected. The mechanism by which Sprouty inhibits Ras activation may be by blocking the nucleotide exchange activity of Sos. Sprouty expression is induced by growth factor receptor activation of Ras signaling, provided a self-regulatory feedback inhibition mechanism that regulates growth factor signaling through Ras.
In addition to blocking the Ras pathway, Sprouty also induces protein tyrosine phosphatase 1B activity. Activation of PTP1B by Sprouty is responsible for the inhibition of cellular migration that Sprouty causes, but is not involved in regulation of cellular proliferation. While blocking receptor tyrosine kinase signaling, at least one member of the Sprouty family, Sprouty-2, also acts by one mechanism to stimulate EGF receptor signaling. Cbl targets the EGF receptor for tagging with ubiquitin and proteolytic destruction. Sprouty-2 binds to Cbl and blocks the ubiquitination and destruction of the EGF receptor, increasing EGF signaling.
Egan JE, Hall AB, Yatsula BA, Bar-Sagi D. The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6041-6.
Fiorini M, Alimandi M, Fiorentino L, Sala G, Segatto O. Negative regulation of receptor tyrosine kinase signals. FEBS Lett. 2001 Feb 16;490(3):132-41. Review.
Glienke J, Fenten G, Seemann M, Sturz A, Thierauch KH. Human SPRY2 inhibits FGF2 signalling by a secreted factor. Mech Dev. 2000 Aug;96(1):91-9.
Gross I, Bassit B, Benezra M, Licht JD. Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J Biol Chem. 2001 Dec 7;276(49):46460-8.
Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G. Mammalian sprouty-1 and -2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol. 2001 Mar 5;152(5):1087-98.
Lee SH, Schloss DJ, Jarvis L, Krasnow MA, Swain JL. Inhibition of angiogenesis by a mouse sprouty protein. J Biol Chem. 2001 Feb 9;276(6):4128-33.
Lim J, Wong ES, Ong SH, Yusoff P, Low BC, Guy GR. Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain. J Biol Chem. 2000 Oct 20;275(42):32837-45.
Lim J, Yusoff P, Wong ES, Chandramouli S, Lao DH, Fong CW, Guy GR. The cysteine-rich sprouty translocation domain targets mitogen-activated protein kinase inhibitory proteins to phosphatidylinositol 4,5-bisphosphate in plasma membranes. Mol Cell Biol. 2002 Nov;22(22):7953-66.
Niehrs C, Meinhardt H. Modular feedback. Nature. 2002 May 2;417(6884):35-6. No abstract available.
Wong ES, Lim J, Low BC, Chen Q, Guy GR. Evidence for direct interaction between Sprouty and Cbl. J Biol Chem. 2001 Feb 23;276(8):5866-75.
Yigzaw Y, Cartin L, Pierre S, Scholich K, Patel TB. The C terminus of sprouty is important for modulation of cellular migration and proliferation. J Biol Chem. 2001 Jun 22;276(25):22742-7.
Yigzaw Y, Poppleton HM, Sreejayan N, Hassid A, Patel TB. Protein-tyrosine Phosphatase-1B (PTP1B) Mediates the Anti-migratory Actions of Sprouty. J Biol Chem. 2003 Jan 3;278(1):284-8.
Yusoff P, Lao DH, Ong SH, Wong ES, Lim J, Lo TL, Leong HF, Fong CW, Guy GR. Sprouty2 inhibits the Ras/MAP kinase pathway by inhibiting the activation of Raf. J Biol Chem. 2002 Feb 1;277(5):3195-201.
|
|
