The CIS/JAB family: novel negative regulators of JAK signaling pathways

Yoshimura, Akihiko

doi:10.1038/sj.leu.2401238

Cited by 52 publications

(38 citation statements)

References 36 publications

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“…The membrane proximal intracellular portion of the receptor till amino-acid number 589, that includes the Box 1 region, was shown to be necessary and su cient for DNA synthesis mediated by several of these cytokines including IL-3 (Sato et al, 1993;Tian et al, 1996). This region was also found to be required for the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. Following cytokineinduced hetero-dimerization, this region of the receptor was found to bind to multiple signal-transducing proteins, which include JAKs, STATs, c-Src, phosphotidylinositol-3 kinase as well as Vav (Quelle et al, 1994;Jaster et al, 1997;Yoshimura et al, 1995Yoshimura et al, , 1998Rao and Mufson, 1995;Matsuguchi et al, 1995). The membrane distal domain of the receptor, spanning amino acids 589 ± 881, was shown to be required for growth inhibition that can be induced by some of the cytokines.…”

Section: Interleukin-3 (Il-3) and Its Receptor (Il3-r)mentioning

confidence: 99%

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

et al. 2000

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Hematopoiesis is the cumulative result of intricately regulated signal transduction cascades that are mediated by cytokines and their cognate receptors. Proper culmination of these diverse signaling pathways forms the basis for an orderly generation of di erent cell types and aberrations in these pathways is an underlying cause for diseases such as cancer. Over the past several years, downstream events initiated upon cytokine/ growth factor stimulation have been a major focus of biomedical research. As a result, several key concepts have emerged allowing a better understanding of the complex signaling processes. A group of novel transcription factors, termed signal transducers and activators of transcription (STATs) appear to orchestrate the downstream events propagated by cytokine/growth factor interactions with their cognate receptors. Until recently, the JAK proteins were considered to be the tyrosine kinases, which dictated the levels of phosphorylation and activation of STAT proteins, forming the basis of the JAK-STAT model. However, over the past few years, increasing evidence has accumulated which indicates that at least some of the STAT protein activation may be mediated by members of the Src gene family following cytokine/growth factor stimulation. Studies have demonstrated that the Src-family of tyrosine kinases can phosphorylate and activate certain STAT proteins, in lieu of JAK kinases. In such a scenario, JAK kinases may be more crucial to phosphorylation of the cytokine/growth factor receptors and in the process create docking sites on the receptors for binding of SH2-containing proteins such as STATs, Src-kinases and other signaling intermediates. Tyrosine phosphorylation and activation of STAT proteins can be achieved either by JAKs or Src-kinases depending on the nature of STAT that is being activated. This forms the basis for the JAK-Src-STAT model proposed in this review. The concerted action of JAK kinases, members of the Src-kinase family and STAT proteins, leads to cell proliferation and cell survival, the end-point of the cytokine/growth factor stimulus.

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Section: Interleukin-3 (Il-3) and Its Receptor (Il3-r)mentioning

confidence: 99%

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

et al. 2000

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“…174,175 Some of the Cis family of proteins can bind this region and prevent Jak binding. 176,185 The Src and phosphatidylinositol-3 kinases (PI3K) can also bind this region. 178 In addition, the Vav GDP/GTP exchange protein binds this region which can result in the association of Vav with the Tec protein tyrosine kinase through interactions of Tec's Src homology 2 region (SH2) domains.…”

Section: Functional Regions Of the Receptor ␣ And ␤ Chainsmentioning

confidence: 99%

“…182,183,186,187 The membrane proximal region is also required for the induction of c-myc, cis, pim-1 and oncostatin M (onco M) gene transcription. 122,[175][176][177]179,183,19 Moreover, this membrane proximal region is also sufficient to promote DNA synthesis.…”

Section: Functional Regions Of the Receptor ␣ And ␤ Chainsmentioning

confidence: 99%

“…225 These STAT dimers then translocate to the nucleus where they act as transcription factors by binding regulatory sites within the promoter region of immediate-early genes such as c-myc, ␤-casein and onco M (see below) 176,225 as well as feedback inhibitors of the JAK-STAT pathway (eg cis). 176 Although STAT activation requires tyrosine phosphorylation by Jak kinases or tyrosine kinase receptors, STAT translocation to the nucleus is enhanced by threonine phosphorylation as a result of Raf/MEK/ERK activation. [229][230][231][232] The consequences of activation of this pathway will be discussed later.…”

Section: Figurementioning

confidence: 99%

“…176,[257][258][259][260][261] In addition, expression of Socs proteins appears to be tissue specific. These inhibitors can function either by binding the Jak protein and blocking activity or by binding the cytokine receptors thereby preventing Jak binding and activation.…”

Section: Inhibitors Of Jak and Stat Proteinsmentioning

confidence: 99%

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1999

Leukemia

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Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

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Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency

et al. 2001

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During the last 10 years, an increasing number of genes have been identified whose abnormalities account for primary immunodeficiencies, with defects in development and/or function of the immune system. Among them is the JAK3-gene, encoding for a tyrosine kinase that is functionally coupled to cytokine receptors which share the common gamma chain. Defects of this gene cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T(-)B(+) SCID). Herewith, we present molecular information on the first 27 unique mutations identified in the JAK3 gene, including clinical data on all of the 23 affected patients reported so far. A variety of mutations scattered throughout all seven functional domains of the protein, and with different functional effects, have been identified. Availability of a molecular screening test, based on amplification of genomic DNA, facilitates the diagnostic approach, and has permitted recognition that JAK3 deficiency may also be associated with atypical clinical and immunological features. Development of a structural model of the JAK3 kinase domain has allowed characterization of the functional effects of the various mutations. Most importantly, molecular analysis at the JAK3 locus results in improved genetic counseling, allows early prenatal diagnosis, and prompts appropriate treatment (currently based on hematopoietic stem cell transplantation) in affected families.

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The CIS/JAB family: novel negative regulators of JAK signaling pathways

Cited by 52 publications

References 36 publications

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled

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Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency

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