MTII Flashcards
How do cell surface receptors influence gene transcription
Indirectly
Tyrosine Kinase Receptors
- Receptors that are tyrosine kinases phosphorylate themselves by cross-phosphorylation, leading to recruitment of additional down-stream proteins
- one of the downstream protiens recruited bu PDGF receptor is phospholipase C(gamma)
- another downstream effector recruited by PDGF-receptor is P13-kinase
Phospholipase C(gamma)
- Produces diacylglycerol, which activates protein kinase C
- produces phosphatidyl (1,4,5) triphosphate, which releases Ca2+
Phosphatidyl Inositol 3’ Kinase (PI3-kinase)
- Produces phosphatidyl (3,4,5) triphosphate which recruits and activates BTK and phosphorylates C(gamma) to and on membrane
- Also recruits and activates PDK and Protein Kinase B on membrane
** The general role of autophosphorylation and “trans” phosphorylation of tyrosines in:
○ receptor mediated signaling:
phosphorylated tyrosines recruit mediators through SH2 domains
**The general role of autophosphorylation and “trans” phosphorylation of tyrosines in:
○ in generating protein-protein interactions through SH2 domains
multiple phosphorylated tyrosines on cytoplasmic tail recruits (through SH2 domains) own particular components of signal transduction pathway
**The role of diacyl glycerol in signal transduction
Diacylglycerols
■ Hydrophobic; can diffuse in plane of membrane
■ Stimulates PKC
**The role of protein kinase C in signal transduction
○ PKC
■ Serinethreonine protein kinase
■ Stimulated by simultaneous presence of Ca2+, diacylglycerol, and
phosphatidyl serine
■ Can phosphorylate proteins on serine and threonine residues
■ In brain, targets membrane channels
■ In other tissues, targets transcription factors
■ Example of PKC target
● Transcription factor NFkB
○ Involved in immune cell activation
○ Found with inhibitor IkB
● PKC stimulated by immune cell activators
● Leads indirectly to phosphorylation of IkB and its degradation
● IkB releases NFkB, which can then enter nucleus and turn on
genes
● Role in inflammation
**The SH2/SH3 intracellular signaling cascade and the MAPkinase pathway
GRB2/Drk/Sem5
■ Has SH2 domain and two SH3 domains
■ No known enzymatic activity
■ Associates with cytoplasmic tail of tyrosineautophosphorylated receptors through SH2 domain
■ SH3 domains attract proline blob from SOS
SOS
■ Contains proline blob
■ GDP/GTP exchange activity
■ Interacts with Gproteins and catalyzes activation by replacing inactive GDP with GTP
Ras Proteins
■ Related to alphasubunit trimeric G-proteins, but function as protein monomers
■ Function as selftimed signal transducer Interact with protein kinase cascade
■ Interact with protein kinase cascade
○Activated Ras activates MAP kinase kinase kinase
- MAP kinase kinase kinase is a serine/threonine kinase which phosphorylates MAP kinase kinases
- MAP kinase kinases phosphorylate MAP kinases on threonines and tyrosines
- MAP kinases phosphorylate variety of substrate proteins involved in cell proliferation
■ Jun (transcription factor)
■ Elk1/SRF (transcription factor)
■ Ribosome S6 kinase (involved in upping translation)
Primary signal induced by binding of growth factor is amplified
■ Ultimately leads to induction of cell proliferation
■ Multiple MAPK cascades exist in cells; activated by different signals and have different effects
**The actions of receptors that are serinethreonine protein kinases, guanylyl cyclases, and phosphotyrosine phosphatases
Serine-threonine kinases
■TGFB receptors
● Family of polypeptide “growth factors”
●Have different effects on target cells
○ Can stimulate or inhibit certain cell types
●Acts as chemical attractant for some cell types
●Belong to larger family of structurally related proteins
○ Includes activins and bone morphogenic proteins
■ Activins involved in mesodermal differentiation in vertebrate development
■ Bone morphogenic proteins stimulate bone
formation
●Transmembrane proteins with threonine/serine directed internal kinase domains
● Operate as dimers of type I and type II receptor subunits
●Similar to Jak/STATs, but occur on serine/threonines, not tyrosines
●TGF-B binds to receptor
○Induces type I and II subunits to dimerize
○ Type II subunit phosphorylates type I
○Phosphorylated type I recruits and phosphorylates members of regulated (R) Smad family
■ Smads are cytoplasmic in absence of phosphorylation
■ On phosphorylation by TGFB receptors, RSmads can dimerize with common (C-) Smad 4 partner
○Heterodimer enters cell nucleus and turns on or off specific genes
■ Specific genes regulated depend on identity of RSmad
■ RSmads can be activating or inhibiting
■ Inhibiting RSmads bind to activated receptors and prevent positiveacting Smads from being activated
Guanylyl cyclases
■ Atrial natriuretic peptides (ANP’s)
●Hormones secreted by cardiac muscle cells in response to high blood pressure
● Induce Na+ and water excretion; lowers blood pressure to normal
●ANP receptors are single pass transmembrane proteins with extracellular ANP binding domain and intracellular guanylyl cyclase catalytic domain
●Binding of ANP’s causes cyclase to produce cyclic GMP
●Cyclic GMP binds to specific cyclic GMPdependent kinase
●GMPspecific kinase phosphorylates other proteins on serine or threonine residues
Signals working through regulated proteolysis of transcription factors
Ex: Wnt receptors
■ Wnt= family of extracellular proteins
■ bind to transmembrane receptors: LRP & Frizzled
■ binding of = inhibition of proteolysis of Bcatenin
■ accumulation of Bcatenin leads to binding of to target genes/regulating expression
Ex: Hedgehog
■ family of extracell. proteins that bind to: Patched
■ binding= inhibition of proteolysis of Ci protein
■ cleaved Ci= transcriptional repressor
■ uncleaved Ci= transcriptional activator
General aspects of bacterial two component signal transduction systems as described for chemotaxis
Chemotaxis=signaling
