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Unformatted text preview: 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 signaling A. TGF is formed by cleavage of an inactive secreted precursor (Lodish Fig. 16-3) B. TGF receptors are Ser/Thr protein kinase (Lodish Fig. 16-4) 1. Type III receptors can bind TGF , but it has no enzymatic activity 2. Type II receptors are activated by cross phosphorylation after binding TGF 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 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 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).target genes (Lodish Fig....
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This note was uploaded on 09/03/2009 for the course MCDB 428 taught by Professor Wang during the Winter '08 term at University of Michigan.
- Winter '08
- cell biology