Barbieri Flashcards
Basics of cell signaling and PTMs
Phenotypic and genotypic remodeling in basal signalosome
Phenotypic: 1. cell signaling via PTM 2. alteration in expression levels of individual signaling components
Genotypic: 1. mutations in signaling components
Cell communication through electrical and chemical signaling mechanisms
- gap junctions that communicate by passing electrical current
- diffusion of second messengers - one cell releases stimulus/repressor which diffuses to target cell w/receptors
General properties of cell signaling pathways
Stimuli act on cell-surface receptors
Transducers which use amplifiers to generate internal messengers that act locally or diffuse
Messengers that engage sensors coupled to effectors that activate cellular responses
How cell stimuli are released from cells
- membrane anchored stimuli released by ectoderm shedding
2. stimuli formed in cytoplasm are packaged into vesicles and released by exocytosis
4 main modes of stimuli action
- juxtacrine: membrane-anchored stimuli activate receptors on neighboring cells
- autocrine: stimuli that are released activate receptors on same cell
- paracrine: stimuli activate neighboring cells
- endocrine: stimuli enter blood stream to act on distanced cells
3 major mechanisms for cell signaling
- receptor-tyrosine kinases
- GPCRs
- Channels
Receptor Tyrosine Kinase- EGF example
EGF precursors located in PM that are cleaved by proteases (such as ADAM proteases). The growth factors then act on EGF receptors.
GPCRs
Most neurotransmitters and hormones act through GPCRs. GPCRs have 3 subunits (alpha, beta, gamma) to stimulate amplifier such as adenylyl cyclase (AC) to generate cAMP or phospholipase C (PLC) to generate DAG IPsP3
Ion channels as receptors for cell stimuli
Ion channels have all components of signaling pathway (receptor, transducer, and amplification).
Gating of Ca2+ ions changes membrane potential (V) which has a messenger function by altering activity of voltage-operated Ca2+ channels.
Signal Transduction Methods
- Preformed complexes
- Diffusion of signaling elements
- Post-translational modifications
- Proteolytic cleavage
Preformed complexes
Info is transferred from one signaling element to the next through conformational coupling.
EX: association of voltage-operated Ca2+ channels with the proteins responsible for exocytosis of synaptic vesicles
Diffusion of signaling elements
- 2nd messengers (Ca2+, cAMP, cGMP)
- Proteins like extracellular signal regulated kinase 1/2 (ERK1/2)
- activated transcription factors translocating to cytoplasm into nucleus
Proteolytic cleavage
- hormone precursors that activate peptides
2. protein degradation
PTMs
PTM modulate component A, which then acts on component B to bring about a conformational change.
Include a host of modifications.
Phosphoylation
- most common PTM
- occurs at serine, threonine, and tyrosine
- tyrosine phosphorylation heavily studied, prevalent in a lot of human disease via receptor tyrosine kinase
Mechanism of phosphorylation
- Serine, threonine, and tyrosine have a nucleophilic (-OH) group that attacks the terminal phosphate group (-PO3) on an ATP donor. This transfers PO4 to aa side chain which is mediated by Mg2+
- Phosphorylation is reversible and regulates protein function
Lipidation
targets proteins to membranes in organelles, vesicles, and the PM.
4 types of lipidation
- GPI anchor
- N-terminal myristoylation
- S-myristoylation
- S-prenylation
GPI anchor
Membrane bound proteins that function as enzymes to adhesion. They contribute to overall organization of membrane bound proteins, and mediate receptor-mediated signal transduction pathways.
N-myristoylation
Method to give proteins a hydrophobic handle for membrane localization. However, this is not a permanent anchor.
S-palmitoylation
Permanently anchors the protein to the membrane. This can be reversed by thioesterases though.
S-prenylation
Adds a farnesyl or geranylgeranyl group and is hydrolytically stable
Protein ubiquitination in cell signaling and protein degradation
Ub of a protein alters conformation enabling them to carry out various signaling functions in the control of cellular responses.
Ub also marks certain proteins for degradation by the proteasome.
Proteolytic cleavage of hormone precursors
POMC (large polypeptide hormone precursor) cleaved into number of biologically active peptides that can act as hormones or neurotransmitters
