Biomaterial Database

Roles of JAK kinases in human GM-CSF receptor signal transduction. 1996

S Watanabe, and T Itoh, and K Arai

Department of Molecular and Developmental Biology, University of Tokyo, Japan.

The receptors for human interleukin-3 (IL-3) and human granulocyte-macrophage colony-stimulating factor (GM-CSF), hIL-3R, hGM-CSFR, respectively, consists of two subunits, alpha and beta, both of which are members of the cytokine receptor superfamily. Phosphorylation of tyrosine residues in the hGMR beta subunit and several cellular proteins is observed after hGM-CSF stimulation. We analyzed the role of tyrosine residues in the hGMR beta subunit and the nature of tyrosine kinase, JAK2, in hGMR signal transduction using several hGMR beta subunit mutants. In addition to the box1 region, a membrane distal region (a.a. 544-589) of the hGMR beta was required for c-fos activation. Only one tyrosine residue (Tyr577) existed within the region 544 to 589, and substitution of Tyr577 to phenylalanine in GMR beta 589 resulted in loss of c-fos activation. In contrast, the same substitution in a wild type receptor did not affect GM-CSF induced activities such as c-fos messenger RNA (mRNA) induction and proliferation, but the substitution abolished Shc phosphorylation. These results suggest that the activation of Shc is not essential for c-fos activation and several tyrosine residues cooperate for c-fos activation. It is well documented that IL-3 or GM-CSF activate JAK2 in BA/F3 cells. The role of JAK2 in IL-3/GM-CSF functions, however, is largely unknown. We examined the role of JAK2 in GM-CSF induced signaling pathways. Dominant negative JAK2 (delta JAK2) lacking the C-terminus kinase domain suppressed IL-3/GM-CSF induced c-fos activation and c-myc activation and proliferation, suggesting that JAK2 was involved in both signaling pathways. Protein tyrosine phosphatase SHP-2 (also called PTP 1D) and Shc were phosphorylated by IL-3/GM-CSF in BA/F3 cells; however, these phosphorylation events were inhibited by the expression of delta JAK2. Taken together, these results indicate the JAK2 is a primary kinase regulating all the known activities of GM-CSF. JAK2 mediates GM-CSF induced c-fos activation through receptor phosphorylation and Shc/PTP 1D activation.

UI	MeSH Term	Description	Entries
D011505	Protein-Tyrosine Kinases	Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.	Tyrosine Protein Kinase,Tyrosine-Specific Protein Kinase,Protein-Tyrosine Kinase,Tyrosine Kinase,Tyrosine Protein Kinases,Tyrosine-Specific Protein Kinases,Tyrosylprotein Kinase,Kinase, Protein-Tyrosine,Kinase, Tyrosine,Kinase, Tyrosine Protein,Kinase, Tyrosine-Specific Protein,Kinase, Tyrosylprotein,Kinases, Protein-Tyrosine,Kinases, Tyrosine Protein,Kinases, Tyrosine-Specific Protein,Protein Kinase, Tyrosine-Specific,Protein Kinases, Tyrosine,Protein Kinases, Tyrosine-Specific,Protein Tyrosine Kinase,Protein Tyrosine Kinases,Tyrosine Specific Protein Kinase,Tyrosine Specific Protein Kinases
D011518	Proto-Oncogene Proteins	Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.	Cellular Proto-Oncogene Proteins,c-onc Proteins,Proto Oncogene Proteins, Cellular,Proto-Oncogene Products, Cellular,Cellular Proto Oncogene Proteins,Cellular Proto-Oncogene Products,Proto Oncogene Products, Cellular,Proto Oncogene Proteins,Proto-Oncogene Proteins, Cellular,c onc Proteins
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D015398	Signal Transduction	The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.	Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D016178	Granulocyte-Macrophage Colony-Stimulating Factor	An acidic glycoprotein of MW 23 kDa with internal disulfide bonds. The protein is produced in response to a number of inflammatory mediators by mesenchymal cells present in the hemopoietic environment and at peripheral sites of inflammation. GM-CSF is able to stimulate the production of neutrophilic granulocytes, macrophages, and mixed granulocyte-macrophage colonies from bone marrow cells and can stimulate the formation of eosinophil colonies from fetal liver progenitor cells. GM-CSF can also stimulate some functional activities in mature granulocytes and macrophages.	CSF-GM,Colony-Stimulating Factor, Granulocyte-Macrophage,GM-CSF,Histamine-Producing Cell-Stimulating Factor,CSF-2,TC-GM-CSF,Tumor-Cell Human GM Colony-Stimulating Factor,Cell-Stimulating Factor, Histamine-Producing,Colony Stimulating Factor, Granulocyte Macrophage,Granulocyte Macrophage Colony Stimulating Factor,Histamine Producing Cell Stimulating Factor,Tumor Cell Human GM Colony Stimulating Factor
D016187	Receptors, Granulocyte-Macrophage Colony-Stimulating Factor	Receptors that bind and internalize the granulocyte-macrophage stimulating factor. Their MW is believed to be 84 kD. The most mature myelomonocytic cells, specifically human neutrophils, macrophages, and eosinophils, express the highest number of affinity receptors for this growth factor.	Antigens, CD116,CD116 Antigens,GM-CSF Receptors,CD116 Antigen,GM-CSF Receptor,Receptor, Granulocyte-Macrophage Colony-Stimulating Factor,Receptors, GM-CSF,Antigen, CD116,GM CSF Receptor,GM CSF Receptors,Receptor, GM-CSF,Receptor, Granulocyte Macrophage Colony Stimulating Factor,Receptors, GM CSF,Receptors, Granulocyte Macrophage Colony Stimulating Factor
D053614	Janus Kinase 2	A Janus kinase subtype that is involved in signaling from GROWTH HORMONE RECEPTORS; PROLACTIN RECEPTORS; and a variety of CYTOKINE RECEPTORS such as ERYTHROPOIETIN RECEPTORS and INTERLEUKIN RECEPTORS. Dysregulation of Janus kinase 2 due to GENETIC TRANSLOCATIONS have been associated with a variety of MYELOPROLIFERATIVE DISORDERS.	JAK-2 Protein Tyrosine Kinase,JAK2 Protein Tyrosine Kinase,JAK 2 Protein Tyrosine Kinase