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FIGURE 16.1 The heterotrimeric G protein signaling network. (A) The signaling network from the b -adrenergic receptor. The pathway on the left,
outlined in blue, shows how adrenaline can induce through cAMP and PKA (c-AMP dependent kinase) glucose production for the fight or flight response.
On the right, outlined in red, is a second pathway regulated by the same second messenger. cAMP can regulate Epac (the cAMP- and AMP-regulated
exchange factor for RAP1) and lead to the activation of MAP-kinase 1,2 (mitogen-activated-protein kinase 1 and 2). Both PKA and MAPK can in turn
phosphorylate and activate the transcription factor CREB (cAMP response element-binding protein) (adapted from [25] ). (B) A common example with the
complexity of cellular signaling systems. The mammalian cell can be compared to a complex network of signaling pathways resembling the many lines
within the New York City subway system. (C) Many hormones and neurotransmitters interact with receptors coupled to different classes of G proteins. G
protein-coupled receptors (GPCRs) often interact with several G proteins and regulate their downstream effectors to activate different intracellular
responses (adapted from [25] ). (D) The interconnection between the receptors and G proteins generate highly interconnected networks like the one seen in
the center of the diagram representing interactions of FDA-approved drugs and their targets (kindly provided by Dr Ma'ayan).
lead to combinatorial signal specificity at the level of gene
expression [22,26] . Such combinatorial specificity may be
used as a mechanism to establish hierarchy among the
regulated cellular processes. Such hierarchy can include
cell motility preceding a secretion or proliferation
response. In the cytoplasm such interconnectivity is largely
mediated through several regulators guanine nucleotide
exchange factors (GEFs) and GTPase-activating proteins
(GAPs) of small G proteins and the three MAP-kinase
pathways (MAPK 1, 2, p38 and JNK). In a few cases
regulation of phosphatase activity is also used to obtain
connectivity between pathways so as to form networks.
ISOFORMS OF SIGNALING MOLECULES,
SIGNALING INTEGRATION AND SORTING
An important molecular characteristic that enables signal
integration is the presence of isoforms of proteins, where
each one has different inputs but all of which have common
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