Tyrosine phosphorylated

Yamaguchi, H., Hendrickson, W. Structural basis for activation of human kinase Lck upon tyrosine phosphorylation. Nature 384 484-489, 1996. 

Histone phosphorylation is a common posttranslational modification fond in histones, primarily on the N-terminal tails. Phosphorylation sites include serine and threonine residues, tyrosine phosphorylation has not been observed so far. Some phosphorylation events occur locally whereas others occur globally throughout all chromosomes during specific events like mitosis. Histone phosphorylation is catalyzed by kinases. Removal of the phosphoryl groups is catalyzed by phosphatases. 

Insulin Receptor. Figure 1 Structure and function of the insulin receptor. Binding of insulin to the a-subunits (yellow) leads to activation of the intracellular tyrosine kinase ((3-subunit) by autophosphorylation. The insulin receptor substrates (IRS) bind via a phospho-tyrosine binding domain to phosphorylated tyrosine residues in the juxtamembrane domain of the (3-subunit. The receptor tyrosine kinase then phosphorylates specific tyrosine motifs (YMxM) within the IRS. These tyrosine phosphorylated motifs serve as docking sites for some adaptor proteins with SRC homology 2 (SH2) domains like the regulatory subunit of PI 3-kinase. 

Tyrosine phosphorylated IRS interacts with and activates PI 3-kinase [3]. Binding takes place via the SRC homology 2 (SH2) domain of the PI 3-kinase regulatory subunit. The resulting complex consisting of INSR, IRS, and PI 3-kinase facilitates interaction of the activated PI 3-kinase catalytic subunit with the phospholipid substrates in the plasma membrane. Generation of PI 3-phosphates in the plasma membrane reemits phospholipid dependent kinases (PDKl and PDK2) which subsequently phosphorylate and activate the serine/threonine kinase Akt (synonym protein... 

Originally discovered as DNA-binding proteins that mediate interferon signaling, recent data demonstrated that STAT1 can also exert constitutive functions in the nucleus, which do not require STAT activation with tyrosine phosphorylation. Cells lacking STAT1 are... 

Hibbs ML, Tarlinton DM. Armes J. Grail D. Hodgson G, Maghtto R, Stacker SA, Dunn AR Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 1995 83 301-311. Nishizumi H, Yamamoto T Impaired tyrosine phosphorylation and Ca + mobiUzation, but not degranulation, in Lyn-deficient bone marrow-derived mast cells. J Immunol 1997 158 2350-2355. 

KAUFMANN w K (1998) Human topoisomerase 11 function, tyrosine phosphorylation and cell cycles checkpoints , Proc Soc Exp Biol Med, 217, 327-34. 

XU K and thornalley p j (2001) Signal transduction activated by the cancer chemopreventive isothiocyanates cleavage of BID protein, tyrosine phosphorylation and activation of INK , Br J Cancer, 84 670-73. 

Several chemokines have been shown to stimulate tyrosine phosphorylation with evidence for activation of both Src family kinases (40) as well as Jak2/3 (41). However, recent lines of evidence provide compelling evidence that... 

Cohen DI, Tani Y, Tian H, Boone E, Samelson LE, Lane HC. Participation of tyrosine phosphorylation in the cytopathic effect of human immunodeficiency virus-1. Science 1992 256(5056) 542-545. 

Chrzanowska-Wodnicka M, Burridge K. Tyrosine phosphorylation is involved in reorganization of the actin cytoskeleton in response to serum or LPA stimulation. J Cell Sci 1994 107(Pt 12) 3643-3654. 

Molecular insight into the protein conformation states of Src kinase has been revealed in a series of x-ray crystal structures of the Src SH3-SH2-kinase domain that depict Src in its inactive conformation [7]. This form maintains a closed structure, in which the tyrosine-phosphorylated (Tyr527) C-terminal tail is bound to the SH2 domain (Fig. 2). The x-ray data also reveal binding of the SH3 domain to the SH2-kinase linker [adopts a polyproline type II (PP II) helical conformation], providing additional intramolecular interactions to stabilize the inactive conformation. Collectively, these interactions cause structural changes within the catalytic domain of the protein to compromise access of substrates to the catalytic site and its associated activity. Significantly, these x-ray structures provided the first direct evidence that the SH2 domain plays a key role in the self-regulation of Src. 

Figure 2 Depiction of the active ( open ) and inactive ( closed ) conformations of Src kinase based on the analysis of x-ray structures of c-Src tyrosine kinase crystallized in its inactive state [7]. The stabilization of the inactive conformation is influenced by multiple events including intramolecular binding of the tyrosine-phosphorylated C-terminus tail to the SH2 domain as well as interactions between the SH3 domain and the SH2-kinase linker. CT, C-terminal NT, N-terminal. 

Waksman G, Kominos D, Robertson SR, Pant N, Baltimore D, Birge RB, Cowbum D, Hanafusa H, Mayer BJ, Overduin M, Resh MD, Rios CB, Silverman L, Kuriyan J. Crystal structure of the phophotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature 1992 358 646-653. 

In vivo labeling of sea urchin eggs revealed that fertilization results in an eightfold increase in 32P orthophosphate incorporation into tyrosine residues of egg proteins because of an increase in the activity of plasma membrane-bound tyrosine protein kinases (Ribot et al., 1984). Tyrosine phosphorylation is therefore believed to be an important step in the events following fertilization. 

Ben-David, Y., Letwin, K., Tannock, L., Bernstein, A., and Pawson, T. (1991). A mammalian protein kinase with potential for serine/threonine and tyrosine phosphorylation is related to cell cycle regulators. EMBO J. 10 317-325. 

Ferrel, J. E. Jr., Wo, M., Gerhaart, J. C., and Martin, G. S. (1991). Cell cycle tyrosine phosphorylation of p34c 2 and a microtubule-associated protein kinase homolog in Xenopus oocytes and eggs. Mol. Cell. Biol. 11 1965-1971. 

Gould, K. L., and Nurse, P. (1989). Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342 39-45. 

Morla, A. 0., Schreurs, J.,Miyajima, A., and Wang, J. H. J. (1988). Hematopoietic growth factors activate the tyrosine phosphorylation of distinct sets of proteins in interleukin-3-dependent murine cell lines. Mol. Cell. Biol. 8 2214-2218. 

Morla, A. O., Draetta, G., Beach, D., and Wang, J. Y. J. (1989). Reversible tyrosine phosphorylation of cdc2 dephosphorylation accompanies activation during entry into mitosis. Cell 58 193-203. 

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