Tyrosine-599 of the c-Mpl receptor is required for Shc phosphorylation and the induction of cellular differentiation.

Alexander, Warren S.; Maurer, Alexander; Novak, Ulrike; Harrison-Smith, M.

doi:10.1002/j.1460-2075.1996.tb01044.x

Cited by 89 publications

(70 citation statements)

References 54 publications

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“…Mpl Y112 is part of a sequence NHSYLPL where the sequence NHSY comprises the Shc phosphotyrosinebinding (PTB) motif, NXXY (Laminet et al, 1996;van der Geer et al, 1996). Therefore, Shc can bind to Y112 through its PTB motif as previously reported (Alexander et al, 1996;Drachman and Kaushansky, 1997). Two tyrosine residues of the EpoR cytoplasmic domain, Y367 and Y425 are required for the engagement of Gab2 in Epo-induced signaling (Wickrema et al, 1999).…”

Section: Discussionmentioning

confidence: 72%

“…Indeed, Shc, Stat5, Cis, SHP2, SHIP1 proteins are all able to bind to this site. It was previously shown that Y112 in mpl receptor was both a site of receptor phosphorylation and a critical residue for the Tpo-dependent phosphorylation of Shc (Alexander et al, 1996), SHIP and Stat3 (Drachman and Kaushansky, 1997). Presumably, Y112 could also be a binding site for multiple proteins, thereby suggesting that multifunctional docking sites comprising speci®c tyrosine residues such as EpoR Y425 or mpl Y112 could exist in cytokine receptors as well as in tyrosine kinase receptors like Met (Bardelli et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…The activation of mpl by its cognate ligand Tpo leads to the tyrosine phosphorylation of Jak2 and Tyk2 tyrosine kinases, of Stat1, Stat3, Stat5, Shc and of mpl (Drachman et al, 1995;Gurney et al, 1995;Pallard et al, 1995;Sattler et al, 1995). Analysis of the tyrosine residues of mpl important for the recruitment of signaling proteins has shown that phosphorylation of tyrosine 112 (Y112) leads to the recruitment of several proteins including Stat3, Shc and SHIP, whereas phosphorylated Y117 is also capable of partial Stat3 recruitment (Alexander et al, 1996;Drachman and Kaushansky, 1997). We have previously shown that the distal cytoplasmic domain is implicated in the megakaryocyte di erentiation of UT7-mpl cells (Porteu et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo)

et al. 2001

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In this study, we show that upon thrombopoietin (Tpo) stimulation the two adapter proteins Gab1 and Gab2 are strongly tyrosine phosphorylated and associated with Shc, SHP2, PI 3-kinase and Grb2 in mpl-expressing UT7 cells. Although Gab1 and Gab2 seem to mediate overlapping biological signals in many cells, only Gab1 is expressed and phosphorylated in response to Tpo in primary human megakaryocytic progenitors; furthermore, it associates with the same proteins. Although a low level of tyrosine phosphorylated IRS-2 protein is also detected in PI 3-kinase immunoprecipitates, Gab proteins are the essential proteins associated with PI 3-kinase after Tpo stimulation. We demonstrate that, albeit no association is detected between the Tpo receptor mpl and Gab proteins, Y112 located in the Cterminal cytoplasmic domain of mpl is required for Gab1/2 tyrosine phosphorylation. Gab proteins are not tyrosine phosphorylated after Tpo stimulation of UT-7 and Ba/F3 cells expressing a mpl mutant lacking Y112. Moreover, no activation of the PI 3-kinase/Akt pathway is observed in cells expressing this mpl mutant. Finally, we show that this mutant does not allow cell proliferation, thereby con®rming that PI 3-kinase activation is required for Tpo-induced cell proliferation. Oncogene (2001) 20, 2197 ± 2204.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo)

et al. 2001

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“…It has been well established that TPO stimulation results in activation of JAK2, immediately followed by the tyrosine phosphorylation of numerous signaling molecules, including Mpl, STAT3, STAT5, Cbl, Shc, Vav, Raf-1, Ras, MAPK, SHIP, and phosphoinositol 3-kinase (PI3K). 9,[36][37][38] To investigate the possible role of SFKs in Mpl signaling, we used a cytokine-dependent murine cell line, BaF3, which was engineered to express Mpl on the cell surface. The results presented in this study demonstrate that the addition of TPO to BaF3/Mpl cells results in the activation of Lyn kinase.…”

Section: Discussionmentioning

confidence: 99%

Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors

Lannutti

Drachman

2004

Blood

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In this study we demonstrate that thrombopoietin (TPO)-stimulated Src family kinases (SFKs) inhibit cellular proliferation and megakaryocyte differentiation. Using the Src kinase inhibitors pyrolopyrimidine 1 and 2 (PP1, PP2), we show that TPO-dependent proliferation of BaF3/Mpl cells was enhanced at concentrations that are specific for SFKs. Similarly, proliferation is increased after introducing a dominant-negative form of Lyn into BaF3/Mpl cells. Murine marrow cells from Lyndeficient mice or wild-type mice cultured in the presence of the Src inhibitor, PP1, yielded a greater number of mature megakaryocytes and increased nuclear ploidy. Truncation and targeted mutation of the Mpl cytoplasmic domain indicate that Y112 is critical for Lyn activation. Examining the molecular mechanism for this antiproliferative effect, we determined that SFK inhibitors did not affect tyrosine phosphorylation of Janus kinase 2 (JAK2) , IntroductionThrombopoietin (TPO) is an essential hematopoietic cytokine that regulates megakaryocytopoiesis via the activation of its cognate receptor, Mpl, expressed on hematopoietic stem cells and megakaryocytic cells (for reviews, see Drachman, 1 Geddis et al, 2 and Kaushansky 3 ). Like other cytokine receptors, Mpl does not contain a kinase domain but, rather, activates members of the receptor-associated Janus kinase (JAK) family on TPO stimulation. Accumulated evidence shows that JAK2 is critical for megakaryocyte (MK) development and that once activated, JAK2 phosphorylates the fourth tyrosine of the Mpl cytoplasmic domain (Y112) and associated signaling molecules, resulting in the activation of the Jak/signal transducer and activator of transcription (STAT) and Ras/Raf/MAPK pathways. [4][5][6][7][8] The JAK/STAT pathway is essential for TPO-stimulated proliferation, whereas the activation of mitogenactivated protein kinase (MAPK) promotes differentiation, especially during sustained activation. 9,10 TPO activation of both the JAK/STAT and MAPK pathways has been well established in both cell lines and primary cells. [11][12][13] However, the complexity of signaling networks suggests that other cellular kinases, such as the Src family of tyrosine kinases, may be activated following TPO/Mpl interaction.The Src kinase family consists of 8 members (Src, Yes, Fgr, Fyn, Lck, Lyn, Blk, and Hck) that regulate a variety of cellular functions including proliferation, differentiation, and migration, depending on cellular milieu. 14,15 Comparison of all 8 Src family kinases (SFKs) reveals a modular organization that determines subcellular organization, protein-protein interactions, and function. 16 The amino-terminal myristoylation and palmitoylation sequences direct SFKs to the inner surface of the cell membrane. The Src homology 3 (SH3) domain directs association with polyproline motifs on interacting signaling molecules, whereas the SH2 domain binds phosphotyrosine residues in a sequence-specific manner. The kinase domain contains an adenosine triphosphate (ATP)-binding site and a catalytic tyrosine re...

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“…[11][12][13][14] The role of JAK2 is still somewhat controversial since one study reported that JAK2, but not TYK2, is necessary for subsequent signaling events, 15 while others have questioned this view. 16 Regardless of such a dispute, Janus kinases, once activated, phosphorylate a number of substrates, including MPL itself which provides a docking site for SH2-containing proteins, the latent transcription factors such as signal transducers and activators of transcription (STAT) 3 and STAT5, and a number of adapter proteins including SHC and SHP2.…”

Section: Introductionmentioning

confidence: 99%

A novel MPL point mutation resulting in thrombopoietin-independent activation

Abe¹,

Suzuki²,

Inagaki³

et al. 2002

Leukemia

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Tyrosine-599 of the c-Mpl receptor is required for Shc phosphorylation and the induction of cellular differentiation.

Cited by 89 publications

References 54 publications

Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo)

Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo)

Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors

A novel MPL point mutation resulting in thrombopoietin-independent activation

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