Biologic Outcome of Jak Stat Activation

Many of the biologic effects of cytokines are mediated by the Stat transcription factors. The Stat proteins are cytoplasmic proteins that are recruited to receptors and activated by tyrosine phosphorylation upon cytokine stimulation before translocating to the nucleus as dimers to initiate transcription of a wide range of genes (Fig. 3). This affects a plethora of cellular activities, as evidenced by the phenotype of mice deficient in Jaks and Stats. Despite the in vitro evidence suggesting a highly redundant system, deletion of individual Jaks and Stats resulted in highly specific effects on

Fig. 3. Structure of Stat protein dimers. Stat proteins bind to the receptor through C-terminal SH2 domains and are phosphorylated on tyrosine (pY) and serine (pY) residues. Stat proteins homo- or heterodimerize by reciprocal SH2-pY interactions and translocate to the nucleus. Stats then bind DNA through the DNA-binding domain to initiate transcription. (Adapted from ref. 128, with permission from J. Kuriyan.)

Fig. 3. Structure of Stat protein dimers. Stat proteins bind to the receptor through C-terminal SH2 domains and are phosphorylated on tyrosine (pY) and serine (pY) residues. Stat proteins homo- or heterodimerize by reciprocal SH2-pY interactions and translocate to the nucleus. Stats then bind DNA through the DNA-binding domain to initiate transcription. (Adapted from ref. 128, with permission from J. Kuriyan.)

cytokine pathways, demonstrating nonredundant roles for these proteins. The results of these gene deletion studies are summarized below and in Table 2.

Jakl-deficient mice are 40% smaller than littermates and die within 24 h of birth, probably as a result of failure of neurogenesis (1). Signaling was ablated in response to IFN-y, IFN-a, and IL-10, as well as cytokines that use the yC and gp130 chains. The absence of IL-7 signaling is thought to be largely responsible for a failure of lymphocyte development with an absence of T-lymphocyte development and a block in B-cell development at the transition from the pro-B to the pre-B cell. The response of Jakl-deficient macrophages, cardiomyocytes, and neurons to gp130 family members IL-6, CT-1, and LIF was severely perturbed.

Jak2 can bind to receptors for TPO, GH, EPO, P-common chain-containing receptors (GM-CSF, IL-3, and IL-5), CT-1, PRL, G-CSF, and gp130-containing receptors (IL-6, CNTF, LIF, and OSM) (2). Disruption of the ubiquitously expressed Jak2 results in embryonic lethality at E12.5 owing to the failure of definitive erythropoiesis (3,4), a phe-notype analogous to but more severe than that observed in mice deficient in the EPO receptor (5). In the presence of EPO and IL-3, Jak2-deficient fetal liver cells failed to produce erythroid colony-forming units (CFU-E), erythroid blast-forming units (BFU-E), and mixed colony-forming units (CFU-Mix). Jak2-null cells failed to respond to TPO, GM-CSF, IL-3, and IFN-y, and the number of progenitors was reduced in response to M-

Gene

Table 2

Phenotype of Mice Deficient for Jak, Stat, and SOCS Proteins

Phenotype

Jak1

Jak2 Jak3 Tyk2 Stat1

Stat2 Stat3

Stat3 (conditional)

Stat4

Stat5a/b

Stat5a

Stat5b Stat6

CIS SOCS1

SOCS2 SOCS3

SOCS6

Postnatal lethal owing to neurologic defect, defects in thymocyte and B-cell production E12.5 embryonic lethal—failure of definitive erythropoiesis Failure of lymphocyte development, increased apoptosis Susceptible to bacteria and viral challenge Susceptible to bacteria and viral challenge and chemically induced tumors, defects in FGF-induced chondrocyte proliferation Susceptible to viral infection E7.5 embryonic lethal owing to defects in mesoderm; IL-6 activates Stat 1 signaling Increased granulocyte production, defects in hepatocyte acute-phase response, survival and proliferation of T cells, neuron survival, skin defects Loss of IL-12 responses; decreased NK cell activity, IFN-y production and Th1 cell formation Female infertility, same as for Stat5a and Stat5b, absent NK cells, reduced myeloid and lymphoid transformation by Tel-Jak2 but not v-Abl or BCR-Abl Defects in mammary growth and lactation, T-cell proliferation, and GM-CSF-induced proliferation of macrophages Defects in NK cell activity, growth, and male-specific gene expression in liver Defects in MHC class II expression, B- and T-cell proliferation, class switching to IgE, Th2 differentiation Viable and fertile Neonatal lethal owing to IFN-y dependent inflammation Gigantism

E 12.5 embryonic lethal owing to placental insufficiency Modest growth retardation

Abbreviations: CIS, cytokine-inducible SH2 containing protein; DC, dendritic cell; FGF, fibroblast growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; NK, natural killer; SOCS, suppressor of cytokine signaling; Stat, signal transducers and activators of transcription.

CSF and SCF. Development of lymphoid populations and responses to gp130-related cytokines and G-CSF were normal. Because of the embryonic lethality, it remains undefined what effect Jak2 deficiency has on PRL and growth hormone signaling.

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