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B Witthuhn

Publications and source records attributed to B Witthuhn.

6 recordsLinked to original sources
PubMed1998

Requirement for Jak3 in mature T cells: its role in regulation of T cell homeostasis.

The tyrosine kinase Jak3 plays a key role in transducing signals from the IL-2, -4, -7, -9, and -15 receptors. Mice lacking Jak3 exhibit a profound, early block in both B and T cell development. To examine the mechanisms whereby Jak3 influences T cell function, we have reconstituted thymic development in Jak3-/- animals by introducing a Jak3 transgene in which expression was driven by the lck proximal promoter. Thymic reconstitution required Jak3 kinase activity, as catalytically inactive Jak3 did not restore early thymic development. Furthermore, the thymus-restricted expression pattern of the transgene allowed us to assess the requirement for Jak3 in peripheral T cells. In these mice, loss of Jak3 expression was associated with a failure to proliferate in response to antigen receptor crosslinking, the accumulation of T cells manifesting an activated cell surface phenotype, and an increased CD4/CD8 ratio among peripheral T cells, all of which are characteristics that were observed in Jak3-/- animals. Finally, we present data which suggest that peripheral T cells proliferate more rapidly in vivo and also undergo apoptosis more rapidly, upon loss of Jak3. Hence Jak3 exerts effects on mature peripheral T lymphocytes, as well as on thymocytes, resulting in the proper maintenance of circulating, quiescent cells.

Animals↗
PubMed1995

Interleukin 4 signals through two related pathways.

The interleukin 4 (IL-4) signaling pathway involves activation, by tyrosine phosphorylation, of two distinct substrates, a signal-transducing factor (STF-IL4) and the IL-4-induced phosphotyrosine substrate (4PS). It is not known whether the IL-4-mediated activation of these substrates occurs via related or distinct signaling pathways. We report that 32D cells, an IL-3-dependent myeloid progenitor cell line in which no phosphorylated 4PS is found, activate high levels of STF-IL4 in response to IL-4. Consistent with the known requirement for 4PS or insulin receptor substrate 1 (IRS-1) in IL-4-mediated mitogenesis, activation of STF-IL4 in 32D cells is not sufficient for IL-4-inducible c-myc expression. In addition, we have examined the ability of 32D cells transfected with different truncation mutants of the human IL-4 receptor to activate Jak-3 kinase and STF-IL4 in response to human IL-4. As in the case of 4PS/IRS-1, we have found that activation of both Jak-3 and STF-IL4 requires the presence of the IL-4 receptor region comprising aa 437-557. The finding that the same region of the IL-4 receptor is required for the induction of both 4PS/IRS-1 and STF-IL4 suggests that the IL-4-stimulated activation of these two substrates might involve common factors.

Animals↗
PubMed1995

A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6.

The protein tyrosine kinases JAK1, JAK2 and Tyk2 and STATs (signal transducers and activators of transcription) 1 and 3 are activated in response to interleukin-6 (IL-6) in human fibrosarcoma cells. In mutant cells lacking JAK1, JAK2 or Tyk2, the absence of one kinase does not prevent activation of the others; activation does not, therefore, involve a sequential three-kinase cascade. In the absence of JAK1, the phosphorylation of the gp130 subunit of the IL-6 receptor and the activation of STATs 1 and 3 are greatly reduced. JAK1 is also necessary for the induction of IRF1 mRNA, thus establishing a requirement for the JAK/STAT pathway in the IL-6 response. JAK2 and Tyk2 although activated cannot, in the absence of JAK1, efficiently mediate activation of STATs 1 and 3. A kinase-negative mutant of JAK2 can, however, inhibit such activation, and ancillary roles for JAK2 and Tyk2 are not excluded. A major role for JAK1 and the nonequivalence of JAK1 and JAK2 in the IL-6 response pathway are, nevertheless, clearly established for these cells.

Adolescent↗
PubMed1994

Cytokine receptors and signal transduction.

The past few years have seen an explosion in the identification, cloning and characterization of cytokines and their receptors. The pleiotropic effects of many of the growth factors and the considerable redundancy in the actions of growth factors have contributed to a mass of descriptive literature that often seems to defy summary. Only recently have common concepts begun to emerge. First, cytokines mediate their effects through a large family of receptors that have evolved from a common progenitor and retain structural and functional similarities. Within the haematopoietic system, the cytokines are not usually instructive in differentiation, but rather supportive, and may contribute to some differentiation-specific responses. The patterns of expression of cytokine receptors are therefore a product of differentiation and provide for changes in physiological regulation. The second important concept that is emerging is that the cytokines mediate their mitogenic effects through a common signal-transducing pathway involving tyrosine phosphorylation. Thus, although the cytokine receptor superfamily members do not have intrinsic protein tyrosine kinase activity, by coupling to activation of tyrosine phosphorylation they may affect cell growth by pathways that are common with the large family of growth factor receptors that contain intrinsic protein tyrosine kinase activity. The coupling of cytokine binding to tyrosine phosphorylation and mitogenesis requires a relatively small membrane-proximal domain of the receptors. This region has limited sequence similarity which may be required for the association of individual receptors with an appropriate kinase. Activation of kinase activity results from the dimerization or oligomerization of receptor homodimers or heterodimers. Again this requirement is similar to that seen with the growth factor receptors which have intrinsic protein tyrosine kinase activity. The protein tyrosine kinases that couple cytokine binding to tyrosine phosphorylation are members of the Jak family of kinases. The ubiquitous expression of these kinases provides a common cellular background on which the cytokine receptors can function and on which unique functionally distinct receptors have evolved. In particular, tyk2 is required for the responses initiated by IFN-alpha while Jak2 has been implicated in the responses to G-CSF, IL-3, EPO, growth hormone, prolactin and IFN-gamma.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1994

The identification of JAK2 tyrosine kinase as a signaling molecule for growth hormone.

The intracellular pathways by which the binding of growth hormone (GH) to its receptor elicits its diverse effects have eluded investigators for many years. Studies showing that GH rapidly stimulates tyrosyl phosphorylation of cellular proteins, and that tyrosine kinase activity co-purifies with GH-GH receptor complexes, led us to hypothesize that activation by GH of a receptor-associated tyrosine kinase is an important early, and perhaps, initiating step in signal transduction by GH. Here, we review the work identifying JAK2 as a GH receptor-associated tyrosine kinase that is rapidly activated by ligand binding.

Animals↗