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Signaling II _Chap 16_ note

Signaling II _Chap 16_ note - Signaling II Signaling...

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Signaling II: Signaling pathways that control gene activity (Lodish Chapter 16) I. Two types of protein kinases and phosphatases in signal transduction A. Protein phosphorylation plays a critical role in regulating protein activity in the cell, especially in the signal transduction pathways. The enzyme, which adds phosphate onto a protein, is called kinase; the enzyme, which removes phosphate from a protein, is called phosphatase (Lodish Fig. 3-33). B. Protein kinases 1. Serine/threonine kinases: phosphorylate serine and threonines residues. Mostly cytosolic, such as the mitotic kinases, a large population (Alberts Fig. 15-66). 2. Tyrosine kinases: phosphorylate tyrosine residue. Receptor tyrosine kinases are the largest population. A list of tyrosine receptor kinase (Alberts Table 15-4, Fig. 15-66) C. Protein phosphatases 1. Serine/threonine phosphatases: dephosphorylate serine and threonines residues. 5 types: PP1, PP2A, PP2B (also called calcineurin, Ca2+ dependent, enriched in neuronal tissues), PP4 and PP5. PP4 and PP5 are much less abundant in the cell. 2. Tyrosine phosphatases (PTPs): dephosphorylate tyrosine residue. II. TGF β signaling A. TGF β is formed by cleavage of an inactive secreted precursor (Lodish Fig. 16-3) B. TGF β receptors are Ser/Thr protein kinase (Lodish Fig. 16-4) 1. Type III receptors can bind TGF β , but it has no enzymatic activity 2. Type II receptors are activated by cross phosphorylation after binding TGF β 3. Type II receptors then phosphorylate and activate type I receptors, which then form a complex with types II and III receptors. 4. Type I then phosphorylates proteins of the Smad family (Smad2 or 3) 5. P-Smads bind to Smad4 and translocate to the nucleus, where they bind DNA to activate gene expression. C. TGF β signaling often blocks cell proliferation so factors that block its activity can function as oncogenes. 1. One such example is Ski, which can bind to Smad3/Smad4 and recruit transcriptional repressors (Lodish Fig. 16-5) III. Erythropoietin and red blood cell formation (Cytokine/JAK/STAT pathway) A. Erythropoietin, its receptor, and red blood cells development (Lodish Fig. 16-6, 7) B. Activation of Erythropoietin receptor activates 4 downstream pathways (Lodish Fig. 16-8) 1. STAT transcription factor 2. GRB2 or shc and Ras-MAPK pathway 3. PLC and Ca2+ signaling 4. PI3K and PKB (Akt) pathway C. Knockout of EpoR or JAK2 in mice is lethal (Lodish Fig. 16-9) 1
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IV. Cytokine receptors and JAK kinase action A. Work through several effectors. We will only consider STAT (Lodish Fig. 16-10, 12) B. JAK and STAT were identified through functional complementation in cultured cells (Lodish Fig. 16-13); C. STAT has a SH2 domain that binds to phosphorylated cytokine receptors. They are then phosphorylated by JAK kinase (Lodish Fig. 16-11). Phospho-STAT then dimerizes, which exposes a NLS. Once in the nucleus it can bind DNA and activate transcription of target genes (Lodish Fig. 16-12).
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