P13k

Stall, Stat3 and related transcriptional factors pp90 Rsk 3CH134, junB, tis21 and tis8

MAP kinase phosphatase (3CH134)

Specific gene activation

Figure 1 Possible control mechanisms of IL-11-mediated signal transduction pathways in preadipocytes.

be activated by a variety of growth factors and mitogens. MAPKs and pp90rsk can be activated by IL-11 and related cytokines. pp90rsk is one of the H7-sensitive protein kinases involved in the expression of primary response genes induced by gpl30 family cytokines. In addition to pp90rsk, various H7-sensi-tive kinases may control the expression of primary response genes at either the transcriptional or post-transcriptional level. Src family tyrosine kinases represent an expanding class of closely related intracellular enzymes that participate in the signal transduction pathways of a variety of surface receptors. It has been shown that Src family kinases, such as p60src and p62ycs can be activated by IL-11 in mouse preadipocytes. PI3K, which phosphorylates the D3 position of phosphatidylinositol or its derivatives, has been associated with many cellular processes. IL-11-stimulated cells revealed increased PI3K activity and the increased P13K was found to be associated with tyrosine phosphorylated proteins, including p62ycs. The amount of p62yes associated with PI3K transiently increased in response to IL-11. Recent studies have shown that IL-11 induces Grb2 to bind to p59fyn and JAK2.

Involvement of phosphatases

Phosphatases involved in IL-11 signaling include MAPK phosphatase, SHP-2 and PP2A. IL-11 significantly induces expression of the 3CH134 gene, which encodes a phosphatase with dual specificity that can specifically dephosphorylate and inactivate MAP kinases both in vitro and in vivo. IL-11 has also been shown to stimulate tyrosine phosphorylation of SHP-2, a SH2-containing protein tyrosine phosphatase shown to be important for signaling of different cytokines. The C-terminus of SHP-2 has been shown to associate with several tyrosine phosphorylated proteins including gpl30 and JAK2. The association of SHP-2 and gpl30 or JAK2 can be further induced by IL-11 stimulation. Peptide competition studies suggest different interactions between SHP-2/gpl30 and SHP-2/JAK2. Recent studies have also shown that IL-11 can induce the association of PP2A, PI3K and p62y" to JAK2.

Transcriptional factors involved in IL-11 signaling

STAT (signal transducers and activators of transcription) family transcriptional factors are cytoplasmic proteins which become tyrosine phosphorylated and activated following ligand-receptor interactions and activation of JAK family kinases. STAT1 and associated protiens are tyrosine phosphorylated and translocated to the nucleus following IL-11 treatment in 3T3-L1 mouse preadipocytes. The activation of STAT3 has been demonstrated for other cytokine receptors within the gp!30 family. The activation of primary response genes such as junB and tisl I by IL-11 may require transcriptional factors other than STATs.

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