Ip3

CT MAP Kinase Kinase Kinase CMAP Kinase Kinase^ CMAP KinĂ¼e)^

FIGURE 18 Phosphorylation of tyrosines on a receptor (R) following agonist (A) binding provides docking sites for the attachment of proteins that transduce the hormonal signal. The growth factor binding protein 2 (GRB2) binds to a phosphorylated tyrosine in the receptor and binds at its other end to the nucleotide exchange factor SOS, which stimulates the small G-protein Ras to exchange its GDP for GTP. Thus activated, Ras in turn activates the protein kinase Raf1 to phosphorylate mitogen-activated protein (MAP) kinase and initiate the MAP kinase cascade that ultimately phosphorylates nuclear transcription factors. The y isoform of phospholipase C (PLCy) docks on the phosphorylated receptor and is then tyrosine phosphorylated and activated to cleave phosphatidylinositol 4,5 bisphosphate (PIP2), releasing diacylglycerol (DAG) and inositol trisphosphate (IP3) and activating protein kinase C (PKC).

They remain activated as they slowly convert GTP to GDP, but inactivation can be accelerated by interaction with GTPase-activating proteins (GAPs).

One of the proteins that docks with phosphorylated tyrosine residues is the growth factor binding protein 2 (Grb2). Grb2 is an adaptor protein that has an SH2 group at one end and other binding motifs at its opposite end which enable it to bind other proteins, including a nucleotide exchange factor called Sos. By means of these protein-protein interactions, the activated receptor can thus communicate with Sos, which activates Ras. Ras in turn activates the enzyme Raf kinase which phosphorylates and activates the first of a cascade of MAP kinases that ultimately result in phosphorylation of nuclear transcription factors.

The gamma isoform of phospholipase C is another effector protein that is recruited to tyrosine-phosphory-lated receptors by way of its SH2 group. It is also a substrate for tyrosine kinases and is activated by tyrosine phosphorylation it catalyzes the formation of DAG and IP3 in the same manner as already discussed for the beta isoforms associated with G-protein coupled receptors. In this manner, tyrosine-kinase-dependent receptors stimulate cellular changes that depend on protein kinase C and the calcium/ calmodulin second messenger system, including phos-phorylation of nuclear transcription factors by calmod-ulin kinase (see Fig. 18).

Another mechanism for modifying gene expression involves activation of a family of proteins called Stat (signal transducer and activator of transcription) proteins. The Stat proteins are transcription factors that reside in the cytosol in their inactive state and have an SH2 group that enables them to bind to tyrosine-phosphorylated proteins. Upon tyrosine phosphoryla-tion, Stat proteins dissociate from their docking sites, form homodimers, and migrate to the nucleus, where they activate transcription of specific genes (Fig. 19).

Yet another important mediator of tyrosine kinase signaling is phosphatidylinositol-3 (PI-3) kinase, which catalyzes the phosphorylation of carbon 3 of the inositol of phosphatidylinositol bisphosphate in cell and organelle membranes to form phosphatidylinositol 3,4,5 trisphosphate (PIP3). PI-3 kinase consists of a regulatory subunit that contains an SH2 domain and a catalytic subunit. Binding of the regulatory subunit to phos-phorylated tyrosines of the receptor-associated complex activates the catalytic subunit. Activation of PI-3 kinase plays a key role in transducing signals from tyrosine-kinase-dependent receptors to downstream events. The enzymes activated by PIP3 are protein kinases that regulate cellular metabolism, vesicle trafficking, cyto-skeletal changes, and nucleotide exchange factors that control the activity of the small G-proteins.

FIGURE 19 Hormone receptors (R) associate with the JAK family of cytosolic protein tyrosine kinases (J), and following binding of agonist (A) and dimerization become phosphorylated on tyrosines. Proteins of the STAT family (S) of transcription factors that reside in the cytosol in the unstimulated state bind to the phosphorylated receptor and, upon being tyrosine phosphorylated by JAK, dissociate from the receptor, form homodimers, and migrate to the nucleus where they activate gene transcription.

FIGURE 19 Hormone receptors (R) associate with the JAK family of cytosolic protein tyrosine kinases (J), and following binding of agonist (A) and dimerization become phosphorylated on tyrosines. Proteins of the STAT family (S) of transcription factors that reside in the cytosol in the unstimulated state bind to the phosphorylated receptor and, upon being tyrosine phosphorylated by JAK, dissociate from the receptor, form homodimers, and migrate to the nucleus where they activate gene transcription.

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