The proliferation and survival of hematopoietic cells is strictly regulated by cytokine growth factors that act through receptors of the Type I cytokine receptor family, including erythropoietin (Epo) and its receptor, EpoR. Mitogenic signaling by these receptors depends on activation of Jak tyrosine kinases. However, other required components of this pathway have not been fully identified. In a screen for proteins that interact with EpoR and Jak2, we identified a novel member of the U-box family of ubiquitin ligases. This receptor-associated ubiquitin ligase, RUL, co-precipitated with EpoR from mammalian cells and mediated ubiquitination of EpoR. Also, endogenously expressed RUL was rapidly and transiently phosphorylated on serine after cytokine treatment of factor-dependent hematopoietic cells. Expression of ubiquitin ligase-deficient mutants of RUL inhibited Epo-induced expression of c-myc and bcl-2, two immediate-early genes normally associated with Epo-induced cell growth. Consistent with that finding, expression of mutant RUL also inhibited Epo-dependent proliferation and survival of factor-dependent cells. Together, these observations suggest that RUL is a required component of mitogenic signaling by EpoR. We also show that RUL is phosphorylated in response to growth factors that act through non-cytokine receptors, suggesting that RUL may function as a common regulator of mitogenesis. The proliferation and survival of hematopoietic cells is strictly regulated by cytokine growth factors that act through receptors of the Type I cytokine receptor family, including erythropoietin (Epo) and its receptor, EpoR. Mitogenic signaling by these receptors depends on activation of Jak tyrosine kinases. However, other required components of this pathway have not been fully identified. In a screen for proteins that interact with EpoR and Jak2, we identified a novel member of the U-box family of ubiquitin ligases. This receptor-associated ubiquitin ligase, RUL, co-precipitated with EpoR from mammalian cells and mediated ubiquitination of EpoR. Also, endogenously expressed RUL was rapidly and transiently phosphorylated on serine after cytokine treatment of factor-dependent hematopoietic cells. Expression of ubiquitin ligase-deficient mutants of RUL inhibited Epo-induced expression of c-myc and bcl-2, two immediate-early genes normally associated with Epo-induced cell growth. Consistent with that finding, expression of mutant RUL also inhibited Epo-dependent proliferation and survival of factor-dependent cells. Together, these observations suggest that RUL is a required component of mitogenic signaling by EpoR. We also show that RUL is phosphorylated in response to growth factors that act through non-cytokine receptors, suggesting that RUL may function as a common regulator of mitogenesis. The proliferation and survival of hematopoietic cell lineages is strictly governed by cytokine growth factors that utilize structurally related receptors of the Type I cytokine receptor family. The hematopoietic lineage in which a specific cytokine acts is determined by the expression pattern of its receptor. For example, erythropoietin (Epo), 1The abbreviations used are: Epo, erythropoietin; EpoR, erythropoietin receptor; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; EGF, epidermal growth factor; Erk, extracellular signal-regulated kinase; FBS, fetal bovine serum; G-CSF, granulocyte-colony stimulating factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GST, glutathione S-transferase; HA, hemagglutinin epitope; HGF, hepatocyte growth factor; IL, interleukin; RUL, receptor-associated ubiquitin ligase; PI 3-kinase, phosphatidylinositol-3 kinase; FBS, fetal bovine serum; wt, wild-type; eNOS, endothelial nitric-oxide synthase; siRNA, small interfering RNA. acting through its receptor, EpoR, is largely restricted to supporting the growth of developing erythroid cells, whereas IL-3 promotes the growth of a broad range of immature myeloid cell lineages expressing its receptor. Cells of these lineages exhibit an absolute dependence on their corresponding growth factors and undergo rapid G1 phase cell cycle arrest and apoptotic death in the absence of that growth factor. Thus, these cytokine receptors regulate signaling pathways that directly promote cell cycle progression and inhibit apoptosis. Type I cytokine receptors have universally been shown to mediate their activities through association with, and activation of, Jak family tyrosine kinases (1Ihle J.N. Nature. 1995; 377: 591-594Crossref PubMed Scopus (1145) Google Scholar, 2O'Shea J.J. Gadina M. Schreiber R.D. Cell. 2002; 109: S121-S131Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar). EpoR activates Jak2 through an interaction with its cytoplasmic domain proximal to the plasma membrane (3Witthuhn B.A. Quelle F.W. Silvennoinen O. Yi T. Tang B. Miura O. Ihle J.N. Cell. 1993; 74: 227-236Abstract Full Text PDF PubMed Scopus (1008) Google Scholar, 4Miura O. Nakamura N. Quelle F.W. Witthuhn B.A. Ihle J.N. Aoki N. Blood. 1994; 84: 1501-1507Crossref PubMed Google Scholar). All Epo-dependent responses, including proliferation, are abrogated by disrupting Jak2 activation (4Miura O. Nakamura N. Quelle F.W. Witthuhn B.A. Ihle J.N. Aoki N. Blood. 1994; 84: 1501-1507Crossref PubMed Google Scholar, 5Zhuang H. Patel S.V. He T.C. Sonsteby S.K. Niu Z. Wojchowski D.M. J. Biol. Chem. 1994; 269: 21411-21414Abstract Full Text PDF PubMed Google Scholar). EpoR can also activate other well characterized signaling intermediates, including components of the Ras pathway, Stat transcription factors, and PI 3-kinase (1Ihle J.N. Nature. 1995; 377: 591-594Crossref PubMed Scopus (1145) Google Scholar). In several instances, functional outcomes have been assigned to activation of these signaling pathways. For example, Epo-induced activation of Stat5 has been reported to enhance expression of the anti-apoptotic gene, bcl-X L, and thereby enhance survival of erythroid cells (6Bunting K.D. Bradley H.L. Hawley T.S. Moriggl R. Sorrentino B.P. Ihle J.N. Blood. 2002; 99: 479-487Crossref PubMed Scopus (125) Google Scholar, 7Socolovsky M. Fallon A.E.J. Wang S. Brugnara C. Lodish H.F. Cell. 1999; 98: 181-191Abstract Full Text Full Text PDF PubMed Scopus (618) Google Scholar). Activation of PI 3-kinase is required to override checkpoints in cell cycle progression, and, as such, it promotes proliferation of cells suffering various forms of stress (8Henry M.K. Lynch J.T. Eapen A.K. Quelle F.W. Blood. 2001; 98: 834-841Crossref PubMed Scopus (73) Google Scholar, 9Eapen A.K. Henry M.K. Quelle D.E. Quelle F.W. Mol. Cell. Biol. 2001; 21: 6113-6121Crossref PubMed Scopus (24) Google Scholar). Despite these identified functions, however, EpoR mutants required for and PI 3-kinase activation to promote survival and proliferation of factor-dependent hematopoietic cells F.W. Wang T. Ihle J.N. Mol. Cell. Biol. PubMed Scopus Google Scholar, H. C. Ihle J.N. J. 2001; PubMed Scopus Google Scholar). have been from of other cytokine receptors, including the receptor for IL-3 F.W. N. Witthuhn B.A. M. Ihle J.N. Mol. Cell. Biol. 1994; PubMed Google Scholar, S. J. Ihle J.N. Mol. Cell. Biol. PubMed Scopus Google Scholar, N. N. J. 1993; PubMed Scopus Google Scholar). Thus, Jak activation the identified cytokine that is required to promote survival and the signaling of Jak2 in Epo-induced growth and survival to several immediate-early have been to this signaling For the cytoplasmic domain of EpoR required for Jak2 activation and cell growth also transcription of the immediate-early c-myc and F.W. Wang T. Ihle J.N. Mol. Cell. Biol. PubMed Scopus Google Scholar). This is with the that expression of c-myc and to cells for growth M. S. J. C. T. Cell. Full Text PDF PubMed Scopus Google Scholar). Thus, activation of c-myc and are of a growth mediated by EpoR. In with its to inhibit expression of anti-apoptotic and bcl-X L, through the domain of EpoR M. C. Blood. PubMed Google Scholar, F.W. Wang J. J. Wang Ihle J.N. PubMed Scopus Google Scholar). Thus, and bcl-X are of the survival by a EpoR. pathways by Type I cytokine receptors are to by several including of Jak by and inhibited activation of by and proteins Cell. Mol. 1999; PubMed Scopus Google Scholar). signaling may also by mediated by of receptors, and N. S. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. O. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S.K. J. PubMed Scopus Google Scholar, D.M. Moriggl R. N. S. Ihle J.N. J. PubMed Google Scholar). of these proteins in mediated through of ubiquitin associated with the of proteins Silvennoinen O. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). of proteins is mediated by a PubMed Scopus Google Scholar, 2001; PubMed Scopus Google Scholar). The is the of a the of ubiquitin and a ubiquitin-activating This is an in of and The ubiquitin is to a ubiquitin-conjugating of the ubiquitin from the to on the In this the ubiquitin is for the for In mammalian cells, the identified components of ubiquitination a E1, several and a and of ubiquitin several by of including to and the identified U-box Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The of ubiquitin to proteins a broad range of 2001; PubMed Scopus Google Scholar, Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the characterized of these is the of This is associated with the of through of the ubiquitin For example, receptor and is regulated by mediated by the H. M. S. S. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). through of the ubiquitin have been associated with of function For example, activation by receptors is mediated through the This is through a in which is with through Wang C. C. C. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). activation of the serine which and activates the C. M. J. Nature. 2001; PubMed Scopus Google Scholar). is for and the activation of the transcription factor. Thus, ubiquitination of receptors and signaling proteins can on the activities of signaling pathways. In the we identified a novel receptor-associated ubiquitin ligase, We show that RUL with EpoR, ubiquitination of EpoR, and is phosphorylated on serine in response to Expression of RUL mutants that ubiquitin Epo-induced expression of c-myc and and Epo-dependent proliferation and survival of factor-dependent hematopoietic cells. We also show that RUL is phosphorylated in response to growth factors acting through non-cytokine Together, these observations suggest that RUL is a required component of Epo-dependent signaling and may function as a common regulator of mitogenic signaling pathways. of for a screen was of the cytoplasmic domain of EpoR Lodish H.F. Cell. Full Text PDF PubMed Scopus Google to the domain of in the expression Jak2 O. Witthuhn B.A. Quelle F.W. Yi T. Ihle J.N. S. 1993; PubMed Scopus Google was the expression of this which is of the that is in the of cells the used to screen from a for growth on and from and for growth on with the not the the of Jak2 expression on on and with to by and for expression of the by of with identified through this was and to a to Expression and mutant by as F.W. Wang T. Ihle J.N. Mol. Cell. Biol. PubMed Scopus Google Scholar). was by an the of the EpoR Lodish H.F. Cell. Full Text PDF PubMed Scopus Google in the expression forms of the RUL that from serine to from to of RUL was a of the RUL and mutant RUL with the in the for of expression as F.W. N. Witthuhn B.A. M. Ihle J.N. Mol. Cell. Biol. 1994; PubMed Google Scholar). For expression in mammalian cells, RUL the expression was to expressed proteins to from ubiquitin was by from myeloid cells. This ubiquitin was with a the of the and was the expression and cells expressing EpoR (8Henry M.K. Lynch J.T. Eapen A.K. Quelle F.W. Blood. 2001; 98: 834-841Crossref PubMed Scopus (73) Google and cells O. Ihle J.N. Nakamura T. 1993; PubMed Scopus Google have been and in fetal bovine and IL-3 cells in and cells in of cells was as by the expressing RUL by of cells. cells for their to in and by with cells in and by cell by for expression of RUL proteins in for on expressing and is that expressing has been to the growth of this in with expression from the cells of cytokine and in for to with IL-3 In RUL cells in and for to growth RUL expression with for to with growth In proteins for in ubiquitination cells with proteins a cells in and and proteins with proteins and by with in for for the and the of of mutant RUL in was by and with of mutant RUL in a and The by of that been with for and with proteins by and with and growth cells in and cell with specific the was to cell proteins by and to cell cell directly by with specific and by as by the specific for by with a from the of from on an with the used for and F.W. Wang T. Ihle J.N. Mol. Cell. Biol. PubMed Scopus Google Jak2 (3Witthuhn B.A. Quelle F.W. Silvennoinen O. Yi T. Tang B. Miura O. Ihle J.N. Cell. 1993; 74: 227-236Abstract Full Text PDF PubMed Scopus (1008) Google EpoR and and and was by from cells with for was on and to with for bcl-2, bcl-X L, and GAPDH, as F.W. Wang T. Ihle J.N. Mol. Cell. Biol. PubMed Scopus Google Scholar, F.W. Wang J. J. Wang Ihle J.N. PubMed Scopus Google Scholar). For on a and to as a for The in Epo-induced cells with was The for cells expressing from and a by the to the of the The RUL used in is from of the RUL and in the of RUL proteins in cells that was with the and was used as a for of a to EpoR a of the U-box of novel signaling with EpoR, a was with a the cytoplasmic domain of EpoR and a expression cells the used to screen a and a the In a this mediated of with the of Jak2 expression in these not expression of the and of Thus, the of the to with the EpoR cytoplasmic domain in the of the was to a to a with an of The was to a identified in a screen for J. C. J. 2001; PubMed Scopus Google Scholar). not we that the of this to the U-box family of ubiquitin The U-box is a of the domain that and Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the the U-box is to a of and a which by of The U-box to an member of this family, it is two by the the and the 1999; PubMed Scopus Google that the the U-box through the of the the U-box to the U-box with a of from the Z. PubMed Scopus Google Scholar). the U-box family has been the of this functional domain are not fully Thus, it is not the domain of the U-box may its function as a ubiquitin that reported to U-box proteins S. M. M. N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google are in the U-box the of as a ubiquitin ligase, the of to in an in was U-box serine to and mutant expressed as proteins in cells and by and of the of proteins to ubiquitination in which a ubiquitin and and a the ubiquitin shown in ubiquitination of was by the of in the the of the from of that through the of for a ubiquitin ligase, ubiquitination was and required activities in the In to The dependence of ubiquitination on the of a functional U-box that is for the in these Thus, these observations the of as a functional ubiquitin with EpoR in the interaction and EpoR, from of cells transiently with and an EpoR shown in EpoR was by not by the to which the was an to of the with receptors in factor-dependent hematopoietic cells, myeloid cells expressing for with endogenously expressed was in and with the that was by The was also by the from cells of with from cells. and EpoR was also in cells, which proteins shown in EpoR was by from cell not in the of the and EpoR to and not receptor was from of cells. 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Ihle J.N. Nakamura T. 1993; PubMed Scopus Google Scholar). through activation of the receptor tyrosine PubMed Scopus Google whereas receptors for and IL-3 are of the family of cytokine receptors as EpoR. RUL from cells was phosphorylated after treatment with G-CSF, in the signaling pathways by these growth factors is by the of Stat5 in response to IL-3 and of these growth factors of Thus, RUL may a common of growth receptors of In this we identified a novel member of the U-box family of ubiquitin as an This receptor-associated ubiquitin with EpoR in factor-dependent hematopoietic cells, ubiquitination of EpoR, and is phosphorylated serine after growth of RUL ubiquitin shown to inhibit expression of genes associated with growth and survival of factor-dependent cells. expression of mutant RUL was growth in a factor-dependent cell suggesting that RUL may function as of a mitogenic signaling the RUL was in a screen for proteins with endothelial nitric-oxide J. C. J. 2001; PubMed Scopus Google Scholar, J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). in cells was to from plasma membrane to the and RUL co-precipitated with However, it to determined is a functional to this interaction for endogenously expressed RUL not with other forms of suggesting that this interaction may not to RUL function in hematopoietic cells that not 1995; PubMed Scopus Google Scholar). The functional of RUL as a ubiquitin was not reported suggest a for the ubiquitin of RUL in the regulated proliferation of hematopoietic cells on the of RUL U-box mutants to inhibit factor-dependent growth of cells. of RUL to the ubiquitin family is on the of an of the U-box which is by The in the RUL U-box a the and the and may not the of this domain Biol. Full Text Full Text PDF PubMed Scopus Google and The in ubiquitination shown in and the dependence on RUL for EpoR ubiquitination in cells the that RUL is a functional ubiquitin that is on the U-box is this is the the RUL This the the and proteins However, this not a functional in RUL ubiquitin including for ubiquitin and of to determined RUL ubiquitin is directly by activation of cytokine RUL was in cells, ubiquitination of RUL was after EpoR we have Epo-induced in forms of RUL in cells However, we have not been to RUL from cells with several Thus, required to the of cytokine receptor activation on RUL ubiquitination in factor-dependent cells. The of ubiquitination on the of the ubiquitin Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). through proteins for whereas through other in function of ubiquitin of U-box proteins have shown that their activities of through of in to and S. M. M. N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, D.M. J. C. J. Biol. Chem. 2002; Full Text Full Text PDF Scopus Google Scholar). We that RUL and ubiquitination of EpoR of is which in mediated by However, we have not in expression of EpoR associated including Jak2, as a function of expression of mutant RUL and have ubiquitination in the of proteins associated with and IL-3 signaling pathways. EpoR, Jak2, and Stat5 have been reported to of cytokine N. S. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. O. S. C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S.K. J. PubMed Scopus Google Scholar, D.M. Moriggl R. N. S. Ihle J.N. J. PubMed Google Scholar). Jak2 was shown to by a in of the Jak2 Silvennoinen O. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). observations a for ubiquitination in the of cytokine signaling by of the signaling pathways for the growth of RUL mutants ubiquitin a for ubiquitination in survival and The that RUL acts as a regulator of signaling pathways may to the of in ubiquitination directly activates a serine and to activation of the transcription Wang C. C. C. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. J. Nature. 2001; PubMed Scopus Google Scholar). RUL and transcription is by the inhibited expression of c-myc and in cells expressing RUL a mutant a U-box Epo-induced expression of and bcl-X not by suggesting that not in a of of of Epo-induced transcription of RUL in not signaling pathways for expression of immediate-early However, the specific in Epo-induced expression of genes associated with growth and survival and is with the proliferation and apoptotic death of cells. The to expression of c-myc and has not been identified. and IL-3 have been reported to activate T. R. T. T. N. S. C. T. H. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Nature. 2001; PubMed Scopus Google a transcription that can through the of ubiquitin ligases. we have not the of cells expressing mutant RUL, is associated with bcl-X expression M. 2002; PubMed Scopus Google Scholar). Epo-induced expression of these immediate-early genes is this is from receptors that not with Jak2, in cells expressing Jak2 F.W. Wang J. J. Wang Ihle J.N. PubMed Scopus Google Scholar, S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, O. Ihle J.N. Mol. Cell. Biol. 1993; PubMed Scopus Google Scholar). to function as a with to its to inhibit ubiquitination of EpoR as well Epo-induced of Thus, with Jak2, RUL may a required component of signaling pathways expression of c-myc and The rapid and of RUL after cytokine treatment this with the regulated by cytokine the of RUL that this the as other to the receptor including of RUL is related to of signaling pathways is However, the of activities in the regulated transcription of c-myc and RUL and We have that Jak2 can RUL on tyrosine in However, we have that this in hematopoietic cells. that RUL of Jak2 through activation of a serine RUL is not on Jak RUL was phosphorylated treatment of cells. acts through the receptor tyrosine PubMed Scopus Google and proliferation of cells Jak kinases Stat transcription factors O. Ihle J.N. Nakamura T. 1993; PubMed Scopus Google Scholar). Thus, RUL may a common of growth receptors from Consistent with a in proliferation regulated by a of growth factors, we expression of RUL in and The that serine of RUL has not been and serine has not been cytokine receptor However, has been reported to mediate serine of the IL-3 receptor M. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). In this serine of RUL to the for the have a for in signaling EpoR, including in expression of c-myc and M. H. Blood. 1999; PubMed Google Scholar, M. M. T. S. H. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. Blood. PubMed Google Scholar). are in the of RUL, these are in the that is not phosphorylated in response to cytokine these other serine kinases can RUL is is growth may RUL receptor ubiquitination by the E3, has been reported to of by the receptor tyrosine H. M. S. S. Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is that growth of RUL its through ubiquitin In that of RUL is serine a required for RUL ubiquitin in We have to this is phosphorylated in growth hematopoietic cells. EpoR activation in cells ubiquitination of RUL, we have not determined this was associated with of RUL in these cells. the of RUL with mitogenic signaling pathways regulated by cytokine receptors with to the specific of its ubiquitin and the of proteins in factor-dependent hematopoietic cells. However, the of this is by the specific of RUL mutants ubiquitin and the association of RUL with by growth We Quelle for a of the
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