Lecture 16: Signalling through enzyme-linked cell surface receptors Flashcards Preview

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Flashcards in Lecture 16: Signalling through enzyme-linked cell surface receptors Deck (13):
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Receptor tyrosine kinases

• Receptors for a variety of growth factors and hormones • Epidermal growth factor (EGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), insulin, nerve growth factor (NGF) etc.

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Receptor tyrosine kinase activation

• Extracellular ligand(s) bind • Receptor oligomerizes – Usually dimerization • Receptor oligomerization causes enzymatic activation of kinase – Usually autophosphorylation • Autophosphorylated receptor transmits downstream signals – Usually by phosphorylating other protein

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General receptor tyrosine kinase activation

• Ligand is a dimer • Ligand will only bind to a dimer interface (EGF, not shown) • Ligand is oligomerized by association with other molecules

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Protein interaction “modules” involved in kinase signal transduction cascades

• SH2 domain • Src Homology 2 • Phosphotyrosine binding domain • Flanking amino acids help determine specificity • PTB domain • Phosphotyrosine binding domain • SH3 domain • Src Homology 3 • Binds proline rich motifs • PH domain • Pleckstrin Homology domain • Recognizes and associated with membrane lipid • PI 3,4,5 trisphosphate (PIP3)

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Activation of Ras

• Small GTP-binding protein • Important for broadcasting many signaling pathways • Many receptor tyrosine kinases modulate the activity of Ras

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MAP-kinases

• Mitogen Activated Protein Kinase – A mitogen is a signal that tells a cell to divide, compared to a growth factor which mainly stimulates cell growth • Form a signaling module – MAP-kinase-kinase-kinase (Raf-1) – MAP kinase (MEK) – MAP kinase • Prolong the signal from growth factor receptors to promote longer term effects like gene changes in gene expression

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Recruitment of signaling molecules to PIP3

• The production of specific inositol lipids by PI 3-kinase generates specific binding sites for other signaling molecules • Proteins containing a “PH-domain” can bind to these sites

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Tyrosine kinases associated receptors

• This class depends on cytoplasmic tyrosine kinases for their activity • The largest family of cytoplasmic tyrosine kinases is the Src family, but there are many others (Janus kinase-Jak, Focal Adhesion Kinase-FAK)

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Receptor serine/threonine kinases

• Transforming Growth Factor β (TGFβ) signaling • Other TGFβ-like ligands include the activins and BMPs (bone morphogenetic proteins) • The type-I receptor also has an associated inhibitory factor that is dissociated by the activated type-II homodimer

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Examples of signaling by regulated proteolysis

Wnt and Notch signalling

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Wnt signalling

A image thumb
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Notch interaction with ligands is regulated by ___

glycosylation

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Other examples of regulated intermembraneous proteolysis 

• Cholesterol sensing 

– Sterol Regulatory Element Binding Protein (SREBP) contains 2 TMD that are selectively cut in response to levels of cholesterol in the membrane 

• Alzheimer’s disease 

– Amyloid Precursor Protein (APP) is cut within its TMD to generate the β-amyloid peptide that is aggregated in the extracellular space of the brain in Alzheimer’s patients 

• Housekeeping functions 

– The transmembrane stubs that are left by signal sequence cleavage are degraded by cleavage within the TMD