Jak2

Transcriptional activation

Ras —>■ MAP kinase —► Transcriptional activation or repression

Elevation of Ca2+

Protein kinase B

_^ Transcriptional activation or repression; modification of other cellular proteins

Transcriptional activation or repression; modification of other cellular proteins

▲ FIGURE 14-9 Overview of signal-transduction pathways triggered by ligand binding to the erythropoietin receptor (EpoR), a typical cytokine receptor. Four major pathways can transduce a signal from the activated, phosphorylated EpoR-JAK complex (see Figure 14-5, bottom). Each pathway ultimately regulates transcription of different sets of genes. (a) In the most direct pathway, the transcription factor STAT5 is phosphorylated and activated directly in the cytosol. (b) Binding of linker proteins (GRB2 or Shc) to an activated EpoR leads to activation of the Ras-MAP kinase pathway. (c, d) Two phosphoinositide pathways are triggered by recruitment of phospholipase C7 and PI-3 kinase to the membrane following activation of EpoR. Elevated levels of Ca2+ and activated protein kinase B also modulate the activity of cytosolic proteins that are not involved in control of transcription.

Somatic Cell Genetics Revealed JAKs and STATs as Essential Signal-Transduction Proteins

Soon after the discovery and cloning of cytokines, most of their receptors were isolated by expression cloning or other strategies. Elucidation of the essential components of their in-tracellular signaling pathways, however, awaited develop-

ment of new types of genetic approaches using cultured mammalian cells. In these studies, a bacterial reporter gene encoding guanine phosphoribosyl transferase (GPRT) was linked to an upstream interferon-responsive promoter. The resulting construct was introduced into cultured mammalian cells that were genetically deficient in the human homolog HGPRT. GPRT or HGPRT is necessary for incorporation of purines

Interferon-responsive promoter

W^ ' M" GPRT ^f Reporter gene construct

Mutagen

HGPRT cells (+ reporter gene) defective for interferon signaling

+ Interferon

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