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Typus
BauernOpfer
Bearbeiter
Graf Isolan
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Untersuchte Arbeit:
Seite: 19, Zeilen: 1-34
Quelle: Sampson et al 2007
Seite(n): 1 (online source), Zeilen: -
[The structural functional analysis of the G-CSFR attributes proliferative signalling to the proximal domain (~60 amino acids proximal to the plasma] membrane) and differentiation signalling to the distal domain (~100 amino acids at the C-terminus)29.

Current models of cytokine receptor signalling, including that for G-CSFR, assign a critical signal transduction role to Janus kinases (Jak). Although Jak2-deficient mice display major defects in IL-3 and GM-CSF signalling, mice deficient in either Jak1 or Jak2 have intact G-CSFR signalling42, 43. The Src family of proto-oncogenic tyrosine kinases seems to have a more important role in transducing G-CSF-induced cell cycle progression. Since Src kinases have a wider range of physiological substrates than do the Jaks, which primarily affect the STAT proteins, Src kinases may play a more important role in G-CSF-mediated cell survival and metabolism. These pathways that involve Erk1/2 or PI3-kinase may contribute to G-CSF-induced proliferation, differentiation, survival and cytoskeletal reorganization29. Multiple protein tyrosine kinases (PTK) (e.g., Jak2 and Src) probably phosphorylate the tyrosine residues (tyr704, tyr729, tyr744 and tyr764) of the G-CSFR44. When phosphorylated, the phosphotyrosine residues serve as docking sites for signalling proteins containing phosphotyrosine binding domains (e.g., SH2 or PTB). Recruitment of these signalling proteins serves to diversify and inactivate G-CSFR signal. Diversification involves recruitment of the STAT transcription factors and Ras/Erk1/2 and PI3-kinase pathways (Fig. 3). Tyr704 can be phosphorylated by the Jaks and then serve as a docking site for the SH2 domains of STAT proteins45. Resembling that site, when phosphorylated, tyr729 may also serve as a docking site for the SH2 domain of STAT. Tyr764 favours the Src kinase and the Src SH2 domain46. This site is also the preferred binding site for the SH2 domains of Grb2 and is functionally coupled to Shc and the SH2-containing tyrosine phosphatise-2 (Shp-2)47. Grb2 also interacts with Gab2, which leads to PI3-kinase activity48. Tyr764 is also functionally coupled to Ras activation and Jun kinase49. Thus, phosphor-tyr764 can transduce several different signals, with both positive and negative effects on growth. Substrate availability and sustained activation may determine functional outcome. In their phosphorylated states, tyr 744 and tyr 729 may serve as docking sites for cytokine inducible SH2 protein/suppressor of cytokine signalling (SOCS) and SH2-containing inositol phosphatese (SHIP)50. Both molecules are negative regulators of Jak-STAT and PI3-kinase, respectively. The C-terminal domain also recruits SH2-containing tyrosine phosphatise-1 (Shp-1), which dephosphorylates positive signalling molecules such as Lyn and STAT51. According to what was said, while there may be a crosstalk between Src and Jak signalling pathways, [each kinase can trigger a stereotyped response, e.g., Jak-STAT and Src-Ras/Pi3-kinase29.]


29. Sampson M, Zhu QS, Corey SJ. Src kinases in G-CSF receptor signaling. Front Biosci. 2007;12:1463-1474.

42. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93:385-395.

43. Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM, Jr., Schreiber RD. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93:373-383.

44. Corey SJ, Dombrosky-Ferlan PM, Zuo S, Krohn E, Donnenberg AD, Zorich P, Romero G, Takata M, Kurosaki T. Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor. J Biol Chem. 1998;273:3230-3235.

45. de Koning JP, Dong F, Smith L, Schelen AM, Barge RM, van der Plas DC, Hoefsloot LH, Lowenberg B, Touw IP. The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation. Blood. 1996;87:1335-1342.

46. Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, et al. SH2 domains recognize specific phosphopeptide sequences. Cell. 1993;72:767-778.

47. de Koning JP, Schelen AM, Dong F, van Buitenen C, Burgering BM, Bos JL, Lowenberg B, Touw IP. Specific involvement of tyrosine 764 of human granulocyte colony-stimulating factor receptor in signal transduction mediated by p145/Shc/GRB2 or p90/GRB2 complexes. Blood. 1996;87:132-140.

48. Zhu QS, Robinson LJ, Roginskaya V, Corey SJ. G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses. Blood. 2004;103:3305-3312.

49. Rausch O, Marshall CJ. Tyrosine 763 of the murine granulocyte colony-stimulating factor receptor mediates Ras-dependent activation of the JNK/SAPK mitogen-activated protein kinase pathway. Mol Cell Biol. 1997;17:1170-1179.

50. Hunter MG, Jacob A, O'Donnell L C, Agler A, Druhan LJ, Coggeshall KM, Avalos BR. Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia. J Immunol. 2004;173:5036-5045.

3. THE G-CSF RECEPTOR

[...]

Current models of cytokine receptor signaling, including that for the G-CSF Receptor, assign the critical signal transduction role to the Janus kinases. [...] In distinction to Jak2-deficient mice that display major defects in IL-3, GM-CSF, Epo, and TPO signaling, mice deficient in either Jak1 or Jak2 have intact G-CSF Receptor signaling (22-24). As discussed below, Src kinases have a non-redundant function in transducing G-CSF-induced cell cycle progression. Src kinases have a wider range of physiological substrates than do the Jaks, which primarily affect the STAT proteins (Figure 1). Src kinases may also play a role in G-CSF-mediated survival and metabolism. These pathways that involve the Erk1/2 or PI 3-kinase may contribute to G-CSF-induced differential and cytoskeletal reorganization.

[...]

6. TYROSINE PHOSPHORYLATION OF THE G-CSF RECEPTOR

Structural functional analysis of the G-CSF Receptor attributes proliferative signaling to the proximal domain (~60 amino acids proximal to the plasma membrane) and differentiation to the distal domain (~100 amino acids at the C-terminus) (Figure 1). [...]

Multiple PTK (e.g. Jak2 and Src) probably phosphorylate the tyrosine residues (Tyr704, Tyr729, Tyr744, and Tyr764) of the G-CSF Receptor (16). [...]

When phosphorylated, the phosphotyrosine residues serve as docking sites for signaling proteins containing a phosphotyrosine binding domains (e.g. SH2 or PTB). Recruitment of these signaling proteins serves to diversify and inactivate G-CSF Receptor's signal. Diversification involves recruitment of the STAT transcription factors and Ras/Erk1/2 and PI 3'kinase pathways (Figure 3). Y704VLQ fits the YXXQ motif, which can be phosphorylated by the Jaks and then serve as a docking site for the SH2 domains of STAT proteins (17). Resembling that site, when phosphorylated, Y729GQL may also serve as a docking site for the SH2 domain of STAT. Y764ENL best approximates the YEEI/L motif favored by both the Src kinase and the Src SH2 domain (56, 60). This site is also the preferred binding site (i.e. YpEN) for the SH2 domain of Grb2 and is functionally coupled to Shc and the SH2-containing tyrosine phosphatase-2 (Shp-2)(18). Grb2 also interacts with Gab2, which leads to PI 3'-kinase activity (61). Tyr764 is also functionally coupled to Ras activation and Jun kinase (62). Thus, phospho-Tyr764 can transduce several different signals with both positive and negative effects on growth. Substrate availability and sustained activation may determine functional outcome. In their phosphorylated states, Y744LRC and Y729GQL may serve as docking sites for cytokine inducible SH2 protein (CIS)/suppressor of cytokine signaling (SOCS) and SH2-containing inositol phosphatase (SHIP) (63-66). Both molecules are negative regulators of Jak-STAT and PI 3'-kinase, respectively. The C-terminal domain also recruits SH2-containing tyrosine phosphatase-1 (Shp-1), which desphosphorylates positive signaling molecules such as Lyn and STAT (67).

7. INTRACELLULAR SIGNALING IN MYELOID CELLS

[...]

[...] While there may be cross-talk between Src and Jak signaling pathways, each kinase can trigger a stereotyped response, e.g. Jak-STAT and Src-Ras/PI 3-kinase.


16. Corey, S. J., P. M. Dombrosky-Ferlan, S. Zuo, E. Krohn, A. D. Donnenberg, P. Zorich, G. Romero, M. Takata & T. Kurosaki: Requirement of Src kinase Lyn for induction of DNA synthesis by granulocyte colony-stimulating factor. J Biol Chem, 273, 3230-5 (1998) 10.1074/jbc.273.6.3230

17. de Koning, J. P., F. Dong, L. Smith, A. M. Schelen, R. M. Barge, D. C. van der Plas, L. H. Hoefsloot, B. Lowenberg & I. P. Touw: The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation. Blood, 87, 1335-42 (1996)

18. de Koning, J. P., A. M. Schelen, F. Dong, C. van Buitenen, B. M. Burgering, J. L. Bos, B. Lowenberg & I. P. Touw: Specific involvement of tyrosine 764 of human granulocyte colony-stimulating factor receptor in signal transduction mediated by p145/Shc/GRB2 or p90/GRB2 complexes. Blood, 87, 132-40 (1996)

22. Parganas, E., D. Wang, D. Stravopodis, D. J. Topham, J. C. Marine, S. Teglund, E. F. Vanin, S. Bodner, O. R. Colamonici, J. M. van Deursen, G. Grosveld & J. N. Ihle: Jak2 is essential for signaling through a variety of cytokine receptors. Cell, 93, 385-95 (1998) 10.1016/S0092-8674 (00)81167-8

23. Rodig, S. J., M. A. Meraz, J. M. White, P. A. Lampe, J. K. Riley, C. D. Arthur, K. L. King, K. C. Sheehan, L. Yin, D. Pennica, E. M. Johnson, Jr. & R. D. Schreiber: Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell, 93, 373-83 (1998) 10.1016/S0092-8674 (00)81166-6

24. Neubauer, H., A. Cumano, M. Muller, H. Wu, U. Huffstadt & K. Pfeffer: Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell, 93, 397-409 (1998) 10.1016/S0092-8674 (00)81168-X

56. Songyang, Z., S. E. Shoelson, M. Chaudhuri, G. Gish, T. Pawson, W. G. Haser, F. King, T. Roberts, S. Ratnofsky, R. J. Lechleider & et al.: SH2 domains recognize specific phosphopeptide sequences. Cell, 72, 767-78 (1993)

61. Zhu, Q. S., L. J. Robinson, V. Roginskaya & S. J. Corey: G-CSF-induced tyrosine phosphorylation of Gab2 is Lyn kinase dependent and associated with enhanced Akt and differentiative, not proliferative, responses. Blood, 103, 3305-12 (2004)

62. Rausch, O. & C. J. Marshall: Tyrosine 763 of the murine granulocyte colony-stimulating factor receptor mediates Ras-dependent activation of the JNK/SAPK mitogen-activated protein kinase pathway. Mol Cell Biol, 17, 1170-9 (1997)

63. Hunter, M. G., A. Jacob, C. O'Donnell L, A. Agler, L. J. Druhan, K. M. Coggeshall & B. R. Avalos: Loss of SHIP and CIS recruitment to the granulocyte colony-stimulating factor receptor contribute to hyperproliferative responses in severe congenital neutropenia/acute myelogenous leukemia. J Immunol, 173, 5036-45 (2004)

64. van de Geijn, G. J., J. Gits, L. H. Aarts, C. Heijmans-Antonissen & I. P. Touw: G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact. Blood, 104, 667-74 (2004)

65. Hermans, M. H., G. J. van de Geijn, C. Antonissen, J. Gits, D. van Leeuwen, A. C. Ward & I. P. Touw: Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF-induced expansion of myeloid progenitor cells. Blood, 101, 2584-90 (2003)

66. van de Geijn, G. J., J. Gits & I. P. Touw: Distinct activities of suppressor of cytokine signaling (SOCS) proteins and involvement of the SOCS box in controlling G-CSF signaling. J Leukoc Biol, 76, 237-44 (2004)

Anmerkungen

Though the source is named in passing nothing has been marked as a citation.

Note that also all the references to the literature have been taken from the source.

Sichter
(Graf Isolan), Hindemith

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