Transforming Growth Factor-ß (TGF-ß) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic Fibrosis in Coordination with the SMAD Pathway.

Transforming growth factor-ß (TGF-ß) signals through both SMAD and non-SMAD pathways to elicit a wide array of biological effects. Existing data have shown the association and coordination between STATs and SMADs in mediating TGF-ß functions in hepatic cells, but it is not clear how STATs are activated under these circumstances. Here, we report that JAK1 is a constitutive TGFßRI binding protein and is absolutely required for phosphorylation of STATs in a SMAD-independent manner within minutes of TGF-ß stimulation. Following the activation of SMADs, TGF-ß also induces a second phase of STAT phosphorylation that requires SMADs, de novo protein synthesis, and contribution from JAK1. Our global gene expression profiling indicates that the non-SMAD JAK1/STAT pathway is essential for the expression of a subset of TGF-ß target genes in hepatic stellate cells, and the cooperation between the JAK1-STAT3 and SMAD pathways is critical to the roles of TGF-ß in liver fibrosis.

The Roots of Chronic Posttraumatic Stress Disorder: Childhood Trauma, Information Processing, and Self-protective Strategies.

BACKGROUND: Although childhood endangerment often precedes adult posttraumatic stress disorder (PTSD), the mechanism from danger to disorder is unclear. We proposed a developmental process in which unprotected and uncomforted danger in childhood would be associated with "shortcuts" in information processing that, in adulthood, could result in PTSD if the adult experienced additional exposure to danger. Information processing was defined as the basic associative, dissociative, and integrative processes used by all humans. Individual differences in parents' (or primary caregivers') protective and comforting behavior were expected to force unprotected children to use psychological shortcuts that linked early trauma to later vulnerability for PTSD. METHOD: We compared 22 adults with chronic PTSD to (a) 22 adults with other psychiatric diagnoses and (b) 22 normative adults without any diagnosis, in terms of information processing around childhood danger. The Adult Attachment Interview was used to derive information processing variables, including self-protective strategies, childhood traumas, and depression. RESULTS: The two patient groups differed from the normative group on all variables. Adults with chronic PTSD differed from other psychiatric patients in having more childhood traumas and using more transformations of associative and dissociative processes. Within the PTSD group, there were three psychologically different subgroups. CONCLUSION: Our findings suggest that (1) prediction of risk for adult PTSD may be possible, (2) treatment might be facilitated by provision of a protective and supportive therapist, (3) who included a focus on correction of information processing errors and use of more adaptive strategies, and (4) subgroups of adults with PTSD may require different forms of treatment.

A negative feedback control of transforming growth factor-beta signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204.

Through the action of its membrane-bound type I receptor, transforming growth factor-beta (TGF-beta) elicits a wide range of cellular responses that regulate cell proliferation, differentiation, and apo ptosis. Many of these signaling responses are mediated by Smad proteins. As such, controlling Smad activity is crucial for proper signaling by TGF-beta and its related factors. Here, we show that TGF-beta induces phosphorylation at three sites in the Smad3 linker region in addition to the two C-terminal residues, and glycogen synthase kinase 3 is responsible for phosphorylation at one of these sites, namely Ser-204. Alanine substitution at Ser-204 and/or the neighboring Ser-208, the priming site for glycogen synthase kinase 3 in vivo activity, strengthened the affinity of Smad3 to CREB-binding protein, suggesting that linker phosphorylation may be part of a negative feedback loop that modulates Smad3 transcriptional activity. Thus, our findings reveal a novel aspect of the Smad3 signaling mechanism that controls the final amplitude of cellular responses to TGF-beta.

IL-6 mediated activation of STAT3 bypasses Janus kinases in terminally differentiated B lineage cells.

Cytokine signaling generally occurs through receptors lacking tyrosine kinase activity. Aggregation of receptors leads to activation of receptor associated Janus kinases (Jaks) which in turn phosphorylate members of a family of transcription factors (STATs) that translocate to the nucleus and regulate gene expression. In the case of Interleukin-6 (IL-6), the consensus for signaling in B lineage cells has been that Jak1, Jak2 and Tyk2 are all phosphorylated upon ligand binding and participate in activation of downstream elements, in particular STAT3. In other cell types, Jak1 has been demonstrated to be absolutely required for IL-6 mediated activation of STAT3. In the present studies, we have identified a series of end stage B cell (plasma cell) lines that fail to express Jak1, but phosphorylate STAT3 in response to IL-6. No evidence was found for a requirement of other Jak family members in the activation of STAT3. STAT3 tyrosine phosphorylation was inhibited in a dose dependent manner by the MEK inhibitor U0126, but not by inhibitors of PI-3K or Src kinases. Moreover, STAT3 phosphorylation was similarly inhibited in lines expressing Jak1 wherein Jak1 was phosphorylated upon IL-6 stimulation and Jak1 phosphorylation was not inhibited by U0126. These results indicate that the MAPK pathway plays a critical role in IL-6 mediated tyrosine phosphorylation of STAT3 and suggests that Jak kinases may not be required in this cascade. Thus, it may be important to re-evaluate the role of Jak kinases in other cytokine signaling pathways as well.