Conditional Activation of Janus Kinase (JAK) Confers Factor Independence upon Interleukin-3-dependent Cells

Mizuguchi, Rumiko; Hatakeyama, Masanori

doi:10.1074/jbc.273.48.32297

Cited by 31 publications

(34 citation statements)

References 42 publications

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“…JAK dimerization has been proposed to be required for kinase activation (18,24). Moreover, an N-terminal multimerization domain has been identified within SH2-B, and has been implicated in SH2-B-mediated potentiation of TRKA signaling (30).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine 813 Is a Site of JAK2 Autophosphorylation Critical for Activation of JAK2 by SH2-Bβ

Kurzer¹,

Argetsinger

Zhou

et al. 2004

Molecular and Cellular Biology

100

103

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The tyrosine kinase Janus kinase 2 (JAK2) binds to the majority of the known members of the cytokine family of receptors. Ligand-receptor binding leads to activation of the associated JAK2 molecules, resulting in rapid autophosphorylation of multiple tyrosines within JAK2. Phosphotyrosines can then serve as docking sites for downstream JAK2 signaling molecules. Despite the importance of these phosphotyrosines in JAK2 function, only a few sites and binding partners have been identified. Using two-dimensional phosphopeptide mapping and a phosphospecific antibody, we identified tyrosine 813 as a site of JAK2 autophosphorylation of overexpressed JAK2 and endogenous JAK2 activated by growth hormone. Tyrosine 813 is contained within a YXXL sequence motif associated with several other identified JAK2 phosphorylation sites. We show that phosphorylation of tyrosine 813 is required for the SH2 domain-containing adapter protein SH2-B␤ to bind JAK2 and to enhance the activity of JAK2 and STAT5B. The homologous tyrosine in JAK3, tyrosine 785, is autophosphorylated in response to interleukin-2 stimulation and is required for SH2-B␤ to bind JAK3. Taken together these data strongly suggest that tyrosine 813 is a site of autophosphorylation in JAK2 and is the SH2-B␤-binding site within JAK2 that is required for SH2-B␤ to enhance activation of JAK2.The Janus kinase family of tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) plays an essential role in the signaling by all members of the cytokine receptor superfamily. The JAKs promote growth, proliferation, and/or differentiation of many cell types (1, 15). Activation of the JAKs occurs upon ligand binding to its receptor. Activation is thought to occur as a consequence of two JAK molecules being brought into close enough proximity to allow for rapid trans-phosphorylation of the activation loop of each kinase (15). The activated JAK molecules then phosphorylate multiple targets, including the JAKs themselves, the associated receptors, and multiple signaling molecules such as the signal transducers and activators of transcription (STATs) (4,10,16,17). Dysregulation of JAKs can lead to a host of physiological problems, including diseases of the immune system (6) and cancer (22,29,40).Among the JAKs, JAK2 is activated by more than two-thirds of the known cytokine receptor ligands, including growth hormone (GH), prolactin, erythropoietin, and leptin, making it the most studied of the JAK family members (14). Autophosphorylation of JAK2 is an important step in regulating signaling as it leads to activation of the kinase. Autophosphorylation also results in the production of potential docking sites for downstream signaling molecules containing phosphotyrosine binding Src homology 2 (SH2) domains, such as the adapter protein, SH2-B, and the JAK2 inhibitor suppressor of cytokine signaling 1 (SOCS-1). Identification of the autophosphorylation sites on JAK2, therefore, is critical for advancing our understanding of how these kinases signal, and could provide potential targets for pharmaceutical ...

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Section: Discussionmentioning

confidence: 99%

Tyrosine 813 Is a Site of JAK2 Autophosphorylation Critical for Activation of JAK2 by SH2-Bβ

Kurzer¹,

Argetsinger

Zhou

et al. 2004

Molecular and Cellular Biology

100

103

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“…In agreement with the above studies, overexpression of Ras or STAT5 alone does not confer IL-3 independence whereas concomitant activation of Ras and STAT5 is su cient to confer IL-3 independence. The same group also, elucidated the role of JAK kinase activity in Ras signaling using a TYK2 protein that was modi®ed by the addition of a membrane localization sequence and a chemical dimerizer (coumermycin)-dependent dimerization sequence (Mizuguchi and Hatakeyama, 1998). The modi®ed TYK2, upon activation by dimerization, conferred IL-3 independence to pro-B lymphoid cells that was abolished by expression of dominant negative Ras indicating the mandatory role for Ras proteins as downstream targets of JAK kinase signals.…”

Section: Cross-talk Among Jaks and Components Of Other Signaling Pathmentioning

confidence: 99%

Janus kinases: components of multiple signaling pathways

2000

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“…For protein induction, cells were washed twice with phosphate-bu ered saline (PBS) and cultured in medium containing 5 mM isopropyl-thiogalactopyranoside (IPTG) without Tc for 24 h before cell lysates were prepared. Cells were lysed in ELB bu er (250 mM NaCl, 5 mM EDTA, 50 mM HEPES/pH 7.0, 0.5% NP40, 1 mM PMSF, 10 mg/ml leupeptin, 10 mg/ml aprotinin) and the cell lysates were loaded on a 7.5, 10 or 15% SDS-polyacrylamide gel (SDS ± PAGE) and blotted onto PVDF membrane ®lter as described (Mizuguchi and Hatakeyama, 1998). Proteins were visualized using ECL detection system (NEN).…”

Section: Protein Induction and Immunoblot Analysismentioning

confidence: 99%

Granulocytic differentiation of myeloid progenitor cells by p130, the retinoblastoma tumor suppressor homologue

et al. 1999

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The retinoblastoma protein (pRB) and the related pocket proteins, p107 and p130, play crucial roles in mammalian cell cycle control. Recent studies indicate that these pocket proteins are also involved in cellular di erentiation processes. We demonstrate in this work that the pRB-related p130 selectively accumulates during the in vitro di erentiation of the myeloid progenitor cell, 32Dcl3, into granulocyte in response to granulocytecolony stimulating factor (G-CSF). This G-CSF-dependent granulocytic di erentiation is blocked by the adenovirus E1A oncoprotein, which binds to and inactivates the pRB family of pocket proteins including p130. Furthermore, enforced overexpression of p130 but not pRB inhibits the myeloid cell proliferation that is concomitantly associated with granulocytic di erentiation morphologically characterized by nuclear segmentation. However, simple G1-cell cycle arrest induced by cytokine deprivation or ectopic overexpression of the p27 cyclin-dependent kinase inhibitor, or inhibition of E2F activities by dominant negative DP-1 is not su cient to trigger granulocytic di erentiation. The di erentiationpromoting activity of p130 in myeloid cells requires both the pocket domain and the spacer domain. Our results indicate that the pRB-related p130 plays a critical role in myeloid cell di erentiation and suggest that coupling of cell cycle exit with the cellular di erentiation program may be speci®cally achieved by p130.

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Conditional Activation of Janus Kinase (JAK) Confers Factor Independence upon Interleukin-3-dependent Cells

Cited by 31 publications

References 42 publications

Tyrosine 813 Is a Site of JAK2 Autophosphorylation Critical for Activation of JAK2 by SH2-Bβ

Tyrosine 813 Is a Site of JAK2 Autophosphorylation Critical for Activation of JAK2 by SH2-Bβ

Janus kinases: components of multiple signaling pathways

Granulocytic differentiation of myeloid progenitor cells by p130, the retinoblastoma tumor suppressor homologue

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